https://www.medchemexpress.com/Targets/g-protein-coupled-receptor-kinase-grk.html2026-08-24daily https://www.medchemexpress.com/Targets/NF-κB.html2026-08-24daily https://s3.medchemexpress.com/Targets/MCE-NF-kB-Signaling-Pathway.pngNF-κB transcription factors are critical regulators of immunity, stress responses, apoptosis and differentiation. In mammals, there are five members of the transcription factor NF-κB family: RELA (p65), RELB and c-REL, and the precursor proteins NF-κB1 (p105) and NF-κB2 (p100), which are processed into p50 and p52, respectively. NF-κB transcription factors bind as dimers to κB sites in promoters and enhancers of a variety of genes and induce or repress transcription. NF-κB activation occurs via two major signaling pathways: the canonical and the non-canonical NF-κB signaling pathways[1]. The canonical NF-κB pathway is triggered by signals from a large variety of immune receptors, such as TNFR, TLR, and IL-1R, which activate TAK1. TAK1 then activates IκB kinase (IKK) complex, composed of catalytic (IKKα and IKKβ) and regulatory (NEMO) subunits, via phosphorylation of IKKβ. Upon stimulation, the IKK complex, largely through IKKβ, phosphorylates members of the inhibitor of κB (IκB) family, such as IκBα and the IκB-like molecule p105, which sequester NF-κB members in the cytoplasm. IκBα associates with dimers of p50 and members of the REL family (RELA or c-REL), whereas p105 associates with p50 or REL (RELA or c-REL). Upon phosphorylation by IKK, IκBα and p105 are degradated in the proteasome, resulting in the nuclear translocation of canonical NF-κB family members, which bind to specific DNA elements, in the form of various dimeric complexes, including RELA-p50, c-REL-p50, and p50-p50. Atypical, IKK-independent pathways of NF-κB induction also provide mechanisms to integrate parallel signaling pathways to increase NF-κB activity, such as hypoxia, UV and genotoxic stress. The non-canonical NF-κB pathway is induced by certain TNF superfamily members, such as CD40L, BAFF and lymphotoxin-β (LT-β), which stimulates the recruitment of TRAF2, TRAF3, cIAP1/2 to the receptor complex. Activated cIAP mediates K48 ubiquitylation and proteasomal degradation of TRAF3, resulting in stabilization and accumulation of the NFκB-inducing kinase (NIK). NIK phosphorylates and activates IKKα, which in turn phosphorylates p100, triggering p100 processing, and leading to the generation of p52 and the nuclear translocation of p52 and RELB[2][3]. Reference:[1]. Oeckinghaus A, et al. The NF-kappaB family of transcription factors and its regulation.Cold Spring Harb Perspect Biol. 2009 Oct;1(4):a000034. [2]. Taniguchi K, et al. NF-κB, inflammation, immunity and cancer: coming of age. Nat Rev Immunol. 2018 May;18(5):309-324.[3]. Perkins ND,et al. Integrating cell-signalling pathways with NF-kappaB and IKK function. Nat Rev Mol Cell Biol. 2007 Jan;8(1):49-62.NF-κB Signaling Pathway | MedChemExpresshttps://www.medchemexpress.com https://www.medchemexpress.com/Targets/EGFR.html2026-08-24daily https://www.medchemexpress.com/Targets/c-type-lectin-like-receptor-ctlr.html2026-08-24daily https://www.medchemexpress.com/Targets/Amyloid-β.html2026-08-24daily https://www.medchemexpress.com/Targets/5-Lipoxygenase.html2026-08-24daily https://www.medchemexpress.com/Targets/plasminogen-plasmin.html2026-08-24daily https://www.medchemexpress.com/Targets/PDGFR.html2026-08-24daily https://www.medchemexpress.com/Targets/Bcl-2%20Family.html2026-08-24daily https://s3.medchemexpress.com/Targets/MCE-Bcl-2-Family-Signaling-Pathway.pngBcl-2 family members have been grouped into three classes. The anti-apoptotic subfamily contains the Bcl-2, Bcl-XL, Bcl-w, Mcl-1, Bfl1/A-1, and Bcl-B proteins, which suppress apoptosis and contain all four Bcl-2 homology domains, designated BH1-4. The pro-apoptotic subfamily contain BH1-3 domains, such as Bax, Bak, and Bok. A third class of BH3 only proteins Bad, Bid, Bim, Noxa and Puma have a conserved BH3 domain that can bind and regulate the anti-apoptotic BCL-2 proteins to promote apoptosis [1].The intrinsic pathway is initiated by various signals, principally extracellular stimuli. BH3-only proteins (Bim, Bid, Bad, Noxa, Puma) engage with anti-apoptotic Bcl-2 family proteins to relieve their inhibition of Bax and Bak to activate them. Next, Bax and Bak are oligomerized and activated, leading to mitochondrial outer membrane permeabilization. Once mitochondrial membranes are permeabilized, cytochrome c and/or Smac/DIABLO is released into the cytoplasm, wherein they combine with an adaptor molecule, Apaf-1, and an inactive initiator Caspase, Pro-caspase 9, within a multiprotein complex called the apoptosome. Smac/DIABLO inhibits IAPs to activate Caspase 9. Caspase 9 activates Caspase 3, which is the initiation step for the cascade of Caspase activation. The extrinsic pathway can be activated by cell surface receptors, such as Fas and TNF Receptor, subsequently activating Caspase 8, and leads to Caspase 3 activation and cell demolition. Caspases in turn cleave a series of substrates, activate DNases and orchestrate the demolition of the cell. Bcl-2 family proteins are also found on the endoplasmic reticulum and the perinuclear membrane in hematopoietic cells, but they are predominantly localized to mitochondria [2]. Reference:[1]. Cotter TG, et al. Apoptosis and cancer: the genesis of a research field. Nat Rev Cancer. 2009 Jul;9(7):501-7.[2]. Kang MH, et al. Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res. 2009 Feb 15;15(4):1126-32.Bcl-2 Family Signaling Pathway | MedChemExpresshttps://www.medchemexpress.com https://www.medchemexpress.com/Targets/macrophage-migration-inhibitory-factor-mif.html2026-08-24daily https://www.medchemexpress.com/Targets/photosystem-ii.html2026-08-24daily https://www.medchemexpress.com/Targets/glycine-receptor-glyr.html2026-08-24daily https://www.medchemexpress.com/Targets/Complement%20System.html2026-08-24daily https://www.medchemexpress.com/Targets/Raf.html2026-08-24daily https://www.medchemexpress.com/Targets/endonuclease.html2026-08-24daily https://www.medchemexpress.com/Targets/foxp.html2026-08-24daily https://www.medchemexpress.com/Targets/Glucosidase.html2026-08-24daily https://www.medchemexpress.com/Targets/Aurora%20Kinase.html2026-08-24daily https://www.medchemexpress.com/Targets/ret.html2026-08-24daily https://www.medchemexpress.com/Targets/pi4p5k.html2026-08-24daily https://www.medchemexpress.com/Targets/CDK.html2026-08-24daily https://www.medchemexpress.com/Targets/ap-1.html2026-08-24daily https://www.medchemexpress.com/Targets/STAT.html2026-08-24daily https://www.medchemexpress.com/Targets/DNA%20Methyltransferase.html2026-08-24daily https://www.medchemexpress.com/Targets/PI3K.html2026-08-24daily https://s3.medchemexpress.com/Targets/MCE-PI3K-Signaling-Pathway.pngPhosphatidylinositol 3 kinases (PI3Ks) are a family of lipid kinases that integrate signals from growth factors, cytokines and other environmental cues, translating them into intracellular signals that regulate multiple signaling pathways. These pathways control many physiological functions and cellular processes, which include cell proliferation, growth, survival, motility and metabolism[1]. In the absence of activating signals, p85 interacts with p110 and inhibits p110 kinase activity. Following receptor tyrosine kinase (RTK) or G protein-coupled receptor (GPCR) activation, class I PI3Ks are recruited to the plasma membrane, where p85 inhibition of p110 is relieved and p110 phosphorylates PIP2 to generate PIP3. The activated insulin receptor recruits intracellular adaptor protein IRS1. Phosphorylation of IRS proteins on tyrosine residues by the insulin receptor initiates the recruitment and activation of PI3K. PIP3 acts as a second messenger which promotes the phosphorylation of Akt at Thr308 by PDK-1. RTK activation can also trigger Ras-Raf-MEK-ERK pathway. Activated Akt, ERK and RSK phosphorylate TSC2 at multiple sites to inhibit TSC1-TSC2-TBC1D7, which is the TSC complex that acts as a GTPase-activating protein (GAP) for the small GTPase RHEB. During inhibition of the TSC complex, GTP-loaded RHEB binds the mTOR catalytic domain to activate mTORC1. Glycogen synthase kinase 3β (GSK-3β) activates the TSC complex by phosphorylating TSC2 at Ser1379 and Ser1383. Phosphorylation of these two residues requires priming by AMPK-dependent phosphorylation of Ser1387. Wnt signaling inhibits GSK-3β and the TSC complex, and thus activates mTORC1. mTORC2 is activated by Wnt in a manner dependent on the small GTPase RAC1. Akt activation contributes to diverse cellular activities which include cell survival, growth, proliferation, angiogenesis, metabolism, and migration. Important downstream targets of Akt are GSK-3, FOXOs, BAD, AS160, eNOS, and mTOR. mTORC1 negatively regulates autophagy through multiple inputs, including inhibitory phosphorylation of ULK1, and promotes protein synthesis through activation of the translation initiation promoter S6K and through inhibition of the inhibitory mRNA cap binding 4E-BP1[1][2][3]. PI3Kδ is a heterodimeric enzyme, typically composed of a p85α regulatory subunit and a p110δ catalytic subunit. In T cells, the TCR, the costimulatory receptor ICOS and the IL-2R can activate PI3Kδ. In B cells, PI3Kδ is activated upon crosslinking of the B cell receptor (BCR). The BCR co-opts the co-receptor CD19 or the adaptor B cell associated protein (BCAP), both of which have YXXM motifs to which the p85α SH2 domains can bind. In lumphocytes, BTK and ITK contribute to the activation of PLCγ and promotes the generation of DAG and the influx of Ca2+, which in turn activate PKC and the CARMA1-, BCL 10- and MALT1 containing (CBM) complex. The resulting NF-κB inhibitor kinase (IKK) activation leads to the phosphorylation and the degradation of IκB, and to the nuclear accumulation of the p50-p65 NF-κB heterodimer. MyD88 is an adapter protein that mediates signal transduction for most TLRs and leads to activation of PI3K[4]. Reference:[1]. Thorpe LM, et al. PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting.Nat Rev Cancer. 2015 Jan;15(1):7-24. [2]. Vanhaesebroeck B, et al. PI3K signalling: the path to discovery and understanding.Nat Rev Mol Cell Biol. 2012 Feb 23;13(3):195-203. [3]. Fruman DA, et al. The PI3K Pathway in Human Disease.Cell. 2017 Aug 10;170(4):605-635.[4]. Lucas CL, et al. PI3Kδ and primary immunodeficiencies.Nat Rev Immunol. 2016 Nov;16(11):702-714. PI3K Signaling Pathway | MedChemExpresshttps://www.medchemexpress.com https://www.medchemexpress.com/Targets/sodium-phosphate-cotransporter.html2026-08-24daily https://www.medchemexpress.com/Targets/glutathione-reductase.html2026-08-24daily https://www.medchemexpress.com/Targets/gpr35.html2026-08-24daily https://www.medchemexpress.com/Targets/ATGL.html2026-08-24daily https://www.medchemexpress.com/Targets/enteropeptidase.html2026-08-24daily https://www.medchemexpress.com/Targets/GABA%20Receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/cd1.html2026-08-24daily https://www.medchemexpress.com/Targets/Discoidin%20Domain%20Receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/MCHR1%20(GPR24).html2026-08-24daily https://www.medchemexpress.com/Targets/Angiotensin-converting%20Enzyme%20(ACE).html2026-08-24daily https://www.medchemexpress.com/Targets/programmed-cell-death-4-pdcd4.html2026-08-24daily https://www.medchemexpress.com/Targets/PKA.html2026-08-24daily 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https://www.medchemexpress.com/Targets/atg7.html2026-08-24daily https://www.medchemexpress.com/Targets/proteasome-cap-targeting-chimeras.html2026-08-24daily https://www.medchemexpress.com/Targets/Urotensin%20Receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/melanopsin-receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/nuclear-factor-of-activated-t-cells-nfat.html2026-08-24daily https://www.medchemexpress.com/Targets/DAPK.html2026-08-24daily https://www.medchemexpress.com/Targets/apoc3.html2026-08-24daily https://www.medchemexpress.com/Targets/Aryl%20Hydrocarbon%20Receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/vista.html2026-08-24daily https://www.medchemexpress.com/Targets/icmt.html2026-08-24daily https://www.medchemexpress.com/Targets/organoid.html2026-08-24daily https://www.medchemexpress.com/Targets/Parasite%20.html2026-08-24daily https://www.medchemexpress.com/Targets/ADC%20Linker.html2026-08-24daily https://www.medchemexpress.com/Targets/hepcidin.html2026-08-24daily https://www.medchemexpress.com/Targets/myotonin-protein-kinase-dmpk.html2026-08-24daily https://www.medchemexpress.com/Targets/natriuretic-peptide-receptor-npr.html2026-08-24daily https://www.medchemexpress.com/Targets/CaMK.html2026-08-24daily https://www.medchemexpress.com/Targets/shp2.html2026-08-24daily https://www.medchemexpress.com/Targets/oligopeptide-cotransporter.html2026-08-24daily https://www.medchemexpress.com/Targets/fap.html2026-08-24daily https://www.medchemexpress.com/Targets/IRE1.html2026-08-24daily https://www.medchemexpress.com/Targets/MicroRNA.html2026-08-24daily https://www.medchemexpress.com/Targets/cd22.html2026-08-24daily https://www.medchemexpress.com/Targets/NOD-like%20Receptor%20(NLR).html2026-08-24daily https://www.medchemexpress.com/Targets/trxr.html2026-08-24daily https://www.medchemexpress.com/Targets/shmt.html2026-08-24daily https://www.medchemexpress.com/Targets/gpr171.html2026-08-24daily https://www.medchemexpress.com/Targets/aldolases.html2026-08-24daily https://www.medchemexpress.com/Targets/Opioid%20Receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/atg4.html2026-08-24daily https://www.medchemexpress.com/Targets/pantetheinase.html2026-08-24daily https://www.medchemexpress.com/Targets/IAP.html2026-08-24daily https://www.medchemexpress.com/Targets/dubtac.html2026-08-24daily https://www.medchemexpress.com/Targets/tet-protein.html2026-08-24daily https://www.medchemexpress.com/Targets/dengue-virus.html2026-08-24daily https://www.medchemexpress.com/Targets/EAAT2.html2026-08-24daily https://www.medchemexpress.com/Targets/transcription-factor-erg.html2026-08-24daily https://www.medchemexpress.com/Targets/SGLT.html2026-08-24daily https://www.medchemexpress.com/Targets/emopamil-binding-protein.html2026-08-24daily https://www.medchemexpress.com/Targets/mas-related-g-protein-coupled-receptor-mrgpr.html2026-08-24daily https://www.medchemexpress.com/Targets/pheromones.html2026-08-24daily https://www.medchemexpress.com/Targets/malate-dehydrogenase-mdh.html2026-08-24daily https://www.medchemexpress.com/Targets/tim-3.html2026-08-24daily https://www.medchemexpress.com/Targets/20-alpha-hsd.html2026-08-24daily https://www.medchemexpress.com/Targets/cd2.html2026-08-24daily https://www.medchemexpress.com/Targets/methylenetetrahydrofolate-dehydrogenase-mthfd.html2026-08-24daily https://www.medchemexpress.com/Targets/Glutathione%20Peroxidase.html2026-08-24daily https://www.medchemexpress.com/Targets/cd3.html2026-08-24daily https://www.medchemexpress.com/Targets/aquaporin.html2026-08-24daily https://www.medchemexpress.com/Targets/separase.html2026-08-24daily https://www.medchemexpress.com/Targets/nadph-oxidase.html2026-08-24daily https://www.medchemexpress.com/Targets/o-glcnacase.html2026-08-24daily https://www.medchemexpress.com/Targets/Guanylate%20Cyclase.html2026-08-24daily https://www.medchemexpress.com/Targets/acetolactate-synthase-als.html2026-08-24daily https://www.medchemexpress.com/Targets/neuromedin-u-receptor-nmur.html2026-08-24daily https://www.medchemexpress.com/Targets/foxm1.html2026-08-24daily https://www.medchemexpress.com/Targets/TGF-β%20Receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/foxc.html2026-08-24daily https://www.medchemexpress.com/Targets/GPR139.html2026-08-24daily https://www.medchemexpress.com/Targets/Cannabinoid%20Receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/Oct3_4.html2026-08-24daily https://www.medchemexpress.com/Targets/sos1.html2026-08-24daily https://www.medchemexpress.com/Targets/PTEN.html2026-08-24daily https://www.medchemexpress.com/Targets/VEGFR.html2026-08-24daily https://www.medchemexpress.com/Targets/orphan-gpcr.html2026-08-24daily https://www.medchemexpress.com/Targets/glutaminase.html2026-08-24daily https://www.medchemexpress.com/Targets/mesothelin.html2026-08-24daily https://www.medchemexpress.com/Targets/nuclear-hormone-receptor-4a.html2026-08-24daily https://www.medchemexpress.com/Targets/Target%20Protein%20Ligand-Linker%20Conjugate.html2026-08-24daily https://www.medchemexpress.com/Targets/pyroptosis.html2026-08-24daily https://s3.medchemexpress.com/Targets/MCE-Pyroptosis-Signaling-Pathway.pngPyroptosis Signaling Pathway | MedChemExpresshttps://www.medchemexpress.com https://www.medchemexpress.com/Targets/Xanthine%20Oxidase.html2026-08-24daily https://www.medchemexpress.com/Targets/exosomes.html2026-08-24daily https://www.medchemexpress.com/Targets/CMV.html2026-08-24daily https://www.medchemexpress.com/Targets/ATP%20Citrate%20Lyase.html2026-08-24daily https://www.medchemexpress.com/Targets/ggtase.html2026-08-24daily https://www.medchemexpress.com/Targets/platelet-activating-factor-receptor-pafr.html2026-08-24daily https://www.medchemexpress.com/Targets/slc39-zinc-transporter.html2026-08-24daily https://www.medchemexpress.com/Targets/lag-3.html2026-08-24daily https://www.medchemexpress.com/Targets/cd47.html2026-08-24daily https://www.medchemexpress.com/Targets/COX.html2026-08-24daily https://www.medchemexpress.com/Targets/metal-nanoparticles.html2026-08-24daily https://www.medchemexpress.com/Targets/cd38.html2026-08-24daily https://www.medchemexpress.com/Targets/Vasopressin%20Receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/Dynamin.html2026-08-24daily https://www.medchemexpress.com/Targets/LPL%20Receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/CETP.html2026-08-24daily https://www.medchemexpress.com/Targets/Phosphatase.html2026-08-24daily https://www.medchemexpress.com/Targets/ide.html2026-08-24daily 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https://www.medchemexpress.com/Targets/Aminoacyl-tRNA%20Synthetase.html2026-08-24daily https://www.medchemexpress.com/Targets/Src.html2026-08-24daily https://www.medchemexpress.com/Targets/ao.html2026-08-24daily https://www.medchemexpress.com/Targets/antibody-drug-conjugate-adc.html2026-08-24daily https://www.medchemexpress.com/Targets/GlyT.html2026-08-24daily https://www.medchemexpress.com/Targets/ribotac.html2026-08-24daily https://www.medchemexpress.com/Targets/Ras.html2026-08-24daily https://www.medchemexpress.com/Targets/mettl3.html2026-08-24daily https://www.medchemexpress.com/Targets/pin1.html2026-08-24daily https://www.medchemexpress.com/Targets/DNA%20Alkylator_Crosslinker.html2026-08-24daily https://www.medchemexpress.com/Targets/c-Met_HGFR.html2026-08-24daily https://www.medchemexpress.com/Targets/dihydrofolate-reductase-dhfr.html2026-08-24daily https://www.medchemexpress.com/Targets/mAChR.html2026-08-24daily https://www.medchemexpress.com/Targets/neuropeptide-s-receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/G-quadruplex.html2026-08-24daily https://www.medchemexpress.com/Targets/carboxylesterase.html2026-08-24daily https://www.medchemexpress.com/Targets/cuproptosis.html2026-08-24daily https://s3.medchemexpress.com/Targets/MCE-Cuproptosis-Signaling-Pathway.pngCuproptosis Signaling Pathway | MedChemExpresshttps://www.medchemexpress.com https://www.medchemexpress.com/Targets/oxidative-phosphorylation.html2026-08-24daily https://www.medchemexpress.com/Targets/rxfp-receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/btb-poz-family.html2026-08-24daily https://www.medchemexpress.com/Targets/protein-prenyltransferase.html2026-08-24daily https://www.medchemexpress.com/Targets/hmg-family.html2026-08-24daily https://www.medchemexpress.com/Targets/PIKfyve.html2026-08-24daily https://www.medchemexpress.com/Targets/URAT1.html2026-08-24daily 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https://www.medchemexpress.com/Targets/Estrogen%20Receptor_ERR.html2026-08-24daily https://www.medchemexpress.com/Targets/GPR55.html2026-08-24daily https://www.medchemexpress.com/Targets/autac.html2026-08-24daily https://www.medchemexpress.com/Targets/5-HT%20Receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/apical-sodium-dependent-bile-acid-transporter.html2026-08-24daily https://www.medchemexpress.com/Targets/CXCR.html2026-08-24daily https://www.medchemexpress.com/Targets/galectin.html2026-08-24daily https://www.medchemexpress.com/Targets/pcsk9.html2026-08-24daily https://www.medchemexpress.com/Targets/connexins.html2026-08-24daily https://www.medchemexpress.com/Targets/metap.html2026-08-24daily https://www.medchemexpress.com/Targets/GPR109A.html2026-08-24daily https://www.medchemexpress.com/Targets/ntpdase.html2026-08-24daily https://www.medchemexpress.com/Targets/MAP3K.html2026-08-24daily https://www.medchemexpress.com/Targets/GHSR.html2026-08-24daily https://www.medchemexpress.com/Targets/mTOR.html2026-08-24daily https://s3.medchemexpress.com/Targets/MCE-mTOR-Signaling-Pathway.pngThe mammalian target of rapamycin (mTOR) signaling pathway integrates both intracellular and extracellular signals and serves as a central regulator of cell metabolism, growth, proliferation and survival[1]. mTOR is the catalytic subunit of two distinct complexes called mTORC1 and mTORC2. mTORC1 comprises DEPTOR, PRAS40, RAPTOR, mLST8, mTOR, whereas mTORC2 comprises DEPTOR, mLST8, PROTOR, RICTOR, mSIN1, mTOR[2]. Rapamycin binds to FKBP12 and inhibits mTORC1 by disrupting the interaction between mTOR and RAPTOR. mTORC1 negatively regulates autophagy through multiple inputs, including inhibitory phosphorylation of ULK1 and TFEB. mTORC1 promotes protein synthesis through activation of the translation initiation promoter S6K and through inhibition of the inhibitory mRNA cap binding 4E-BP1, and regulates glycolysis through HIF-1α. It promotes de novo lipid synthesis through the SREBP transcription factors. mTORC2 inhibits FOXO1,3 through SGK and Akt, which can lead to increased longevity. The complex also regulates actin cytoskeleton assembly through PKC and Rho kinase[3]. Growth factors: Growth factors can signal to mTORC1 through both PI3K-Akt and Ras-Raf-MEK-ERK axis. For example, ERK and RSK phosphorylate TSC2, and inhibit it. Insulin Receptor: The activated insulin receptor recruits intracellular adaptor protein IRS1. Phosphorylation of these proteins on tyrosine residues by the insulin receptor initiates the recruitment and activation of PI3K. PIP3 acts as a second messenger which promotes the phosphorylation of Akt and triggers the Akt-dependent multisite phosphorylation of TSC2. TSC is a heterotrimeric complex comprised of TSC1, TSC2, and TBC1D7, and functions as a GTPase activating protein (GAP) for the small GTPase Rheb, which directly binds and activates mTORC1. mTORC2 primarily functions as an effector of insulin/PI3K signaling. Wnt: The Wnt pathway activates mTORC1. Glycogen synthase kinase 3β (GSK-3β) acts as a negative regulator of mTORC1 by phosphorylating TSC2. mTORC2 is activated by Wnt in a manner dependent on the small GTPase RAC1[4]. Amino acids: mTORC1 senses both lysosomal and cytosolic amino acids through distinct mechanisms. Amino acids induce the movement of mTORC1 to lysosomal membranes, where the Rag proteins reside. A complex named Ragulator, interact with the Rag GTPases, recruits them to lysosomes through a mechanism dependent on the lysosomal v-ATPase, and is essential for mTORC1 activation. In turn, lysosomal recruitment enables mTORC1 to interact with GTP-bound RHEB, the end point of growth factor. Cytosolic leucine and arginine signal to mTORC1 through a distinct pathway comprised of the GATOR1 and GATOR2 complexes. Stresses: mTORC1 responds to intracellular and environmental stresses that are incompatible with growth such as low ATP levels, hypoxia, or DNA damage. A reduction in cellular energy charge, for example during glucose deprivation, activates the stress responsive metabolic regulator AMPK, which inhibits mTORC1 both indirectly, through phosphorylation and activation of TSC2, as well as directly through the phosphorylation of RAPTOR. Sestrin1/2 are two transcriptional targets of p53 that are implicated in the DNA damage response, and they potently activate AMPK, thus mediating the p53-dependent suppression of mTOR activity upon DNA damage. During hypoxia, mitochondrial respiration is impaired, leading to low ATP levels and activation of AMPK. Hypoxia also affects mTORC1 in AMPK-independent ways by inducing the expression of REDD1, the protein products of which then suppress mTORC1 by promoting the assembly of TSC1-TSC2[2]. Reference:[1]. Laplante M, et al.mTOR signaling at a glance.J Cell Sci. 2009 Oct 15;122(Pt 20):3589-94. [2]. Zoncu R, et al. mTOR: from growth signal integration to cancer, diabetes and ageing.Nat Rev Mol Cell Biol. 2011 Jan;12(1):21-35. [3]. Johnson SC, et al. mTOR is a key modulator of ageing and age-related disease.Nature. 2013 Jan 17;493(7432):338-45.[4]. Shimobayashi M, et al. Making new contacts: the mTOR network in metabolism and signalling crosstalk.Nat Rev Mol Cell Biol. 2014 Mar;15(3):155-62.mTOR Signaling Pathway | MedChemExpresshttps://www.medchemexpress.com https://www.medchemexpress.com/Targets/ATP%20Synthase.html2026-08-24daily https://www.medchemexpress.com/Targets/lats.html2026-08-24daily https://www.medchemexpress.com/Targets/urea-transporter.html2026-08-24daily https://www.medchemexpress.com/Targets/Histone%20Acetyltransferase.html2026-08-24daily https://www.medchemexpress.com/Targets/ceramidase.html2026-08-24daily https://www.medchemexpress.com/Targets/Btk.html2026-08-24daily https://www.medchemexpress.com/Targets/GSK-3.html2026-08-24daily https://s3.medchemexpress.com/Targets/MCE-GSK-3-Signaling-Pathway.pngGlycogen synthase kinase 3 (GSK-3) is a multifunctional serine/threonine kinase found in all eukaryotes. GSK-3 is one of the few signaling mediators that play central roles in a diverse range of signaling pathways, including those activated by Wnt, PI3K, growth factors, cytokines, and ligands for G protein-coupled receptors. The PI3K pathway is known for regulating metabolism, cell growth, and cell survival. The PI3K activity is stimulated by diverse oncogenes and growth factor receptors. PI3K-mediated production of PIP3 leads to the activation of Akt. The activation of Akt leads to the phosphorylation of GSK-3, which is active in resting cells, but is inactivated by the phosphorylation. The GSK-3 has been linked to the regulation of an assembly of transcription factors, including β-catenin, NF-κB, c-Jun, CREB, and STAT. Thus, the altered activity of GSK-3 causes various effects on cytokine expression. In the absence of Wnt signaling, β-catenin is phosphorylated by CK1 and GSK-3. This phosphorylation leads to recognition by β-TrCP, leading to the ubiquitylation of β-catenin and degradation by the proteasome. Upon binding of a lipid-modified Wnt protein to the receptor complex, a signaling cascade is initiated. LRP is phosphorylated by CK1/CK2 and GSK-3, and Axin is recruited to the plasma membrane. The kinases in the β-catenin destruction complex are inactivated and β-catenin translocates to the nucleus to form an active transcription factor complex with TCF, leading to transcription of a large set of target genes. Some endogenous growth factors could bind to and activate the tyrosine kinase receptor. This facilitates the recruitment of other proteins (SHC, SOS), which results in the activation of the ERK-MAPK cascade and the inhibition of GSK-3. GSK-3 exerts many cellular effects: it regulates cytoskeletal proteins, and is important in determining cell survival/cell death. GSK-3 has also been identified as a target for the actions of lithium. GSK-3 can inhibit glycogen synthase, the enzyme that catalyzes the transfer of glucose from UDPG to glycogen[1][2]. Reference:[1]. Brenner D, et al. Regulation of tumour necrosis factor signalling: live or let die.Nat Rev Immunol. 2015 Jun;15(6):362-74. [2]. Conrad M, et al. Regulated necrosis: disease relevance and therapeutic opportunities.Nat Rev Drug Discov. 2016 May;15(5):348-66. GSK-3 Signaling Pathway | MedChemExpresshttps://www.medchemexpress.com https://www.medchemexpress.com/Targets/Arginase.html2026-08-24daily https://www.medchemexpress.com/Targets/Thyroid%20Hormone%20Receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/erythropoietin-receptor-epor.html2026-08-24daily https://www.medchemexpress.com/Targets/HIV%20Protease.html2026-08-24daily https://www.medchemexpress.com/Targets/14-3-3-protein.html2026-08-24daily https://www.medchemexpress.com/Targets/3-alpha-hsd.html2026-08-24daily https://www.medchemexpress.com/Targets/Fatty%20Acid%20Synthase%20(FAS).html2026-08-24daily https://www.medchemexpress.com/Targets/dagl.html2026-08-24daily https://www.medchemexpress.com/Targets/atf6.html2026-08-24daily https://www.medchemexpress.com/Targets/l-selectin.html2026-08-24daily https://www.medchemexpress.com/Targets/sf3b1.html2026-08-24daily https://www.medchemexpress.com/Targets/fbpase.html2026-08-24daily https://www.medchemexpress.com/Targets/CCR.html2026-08-24daily https://www.medchemexpress.com/Targets/carnitine-palmitoyltransferase-cpt.html2026-08-24daily https://www.medchemexpress.com/Targets/carnosine-cleaving-enzyme.html2026-08-24daily https://www.medchemexpress.com/Targets/odc.html2026-08-24daily https://www.medchemexpress.com/Targets/aba-receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/sniper.html2026-08-24daily https://www.medchemexpress.com/Targets/kisspeptin-receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/mGluR.html2026-08-24daily https://www.medchemexpress.com/Targets/PDHK.html2026-08-24daily https://www.medchemexpress.com/Targets/FABP.html2026-08-24daily https://www.medchemexpress.com/Targets/NO%20Synthase.html2026-08-24daily https://www.medchemexpress.com/Targets/HSP.html2026-08-24daily https://www.medchemexpress.com/Targets/BMX%20Kinase.html2026-08-24daily https://www.medchemexpress.com/Targets/Ephrin%20Receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/mucin.html2026-08-24daily https://www.medchemexpress.com/Targets/endothelin-converting-enzyme-ece.html2026-08-24daily https://www.medchemexpress.com/Targets/Neurokinin%20Receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/ROCK.html2026-08-24daily https://www.medchemexpress.com/Targets/rankl-rank.html2026-08-24daily https://www.medchemexpress.com/Targets/APC.html2026-08-24daily https://www.medchemexpress.com/Targets/aim2.html2026-08-24daily https://www.medchemexpress.com/Targets/Glucocorticoid%20Receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/Monocarboxylate%20Transporter.html2026-08-24daily https://www.medchemexpress.com/Targets/ferroportin.html2026-08-24daily https://www.medchemexpress.com/Targets/gpvi.html2026-08-24daily https://www.medchemexpress.com/Targets/γ-glutamyl-transferase-ggt.html2026-08-24daily https://www.medchemexpress.com/Targets/phytohormone.html2026-08-24daily https://www.medchemexpress.com/Targets/tnk1.html2026-08-24daily https://www.medchemexpress.com/Targets/rev-erb.html2026-08-24daily https://www.medchemexpress.com/Targets/Aminopeptidase.html2026-08-24daily https://www.medchemexpress.com/Targets/PROTAC%20Linker.html2026-08-24daily https://www.medchemexpress.com/Targets/phosphoramidites.html2026-08-24daily https://www.medchemexpress.com/Targets/n-myristoyltransferase.html2026-08-24daily https://www.medchemexpress.com/Targets/Reverse%20Transcriptase.html2026-08-24daily https://www.medchemexpress.com/Targets/Stearoyl-CoA%20Desaturase%20(SCD).html2026-08-24daily https://www.medchemexpress.com/Targets/tssk.html2026-08-24daily https://www.medchemexpress.com/Targets/lysyl-oxidase.html2026-08-24daily https://www.medchemexpress.com/Targets/orphan-receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/photosensitizer.html2026-08-24daily https://www.medchemexpress.com/Targets/Dipeptidyl%20Peptidase.html2026-08-24daily https://www.medchemexpress.com/Targets/amylin-receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/cd20.html2026-08-24daily https://www.medchemexpress.com/Targets/HCV.html2026-08-24daily https://www.medchemexpress.com/Targets/LXR.html2026-08-24daily https://www.medchemexpress.com/Targets/PKD.html2026-08-24daily https://www.medchemexpress.com/Targets/dimethylargininase-ddah.html2026-08-24daily https://www.medchemexpress.com/Targets/α-synuclein.html2026-08-24daily https://www.medchemexpress.com/Targets/Potassium%20Channel.html2026-08-24daily https://www.medchemexpress.com/Targets/ULK.html2026-08-24daily https://www.medchemexpress.com/Targets/dihydropyrimidine-dehydrogenase-dpd.html2026-08-24daily https://www.medchemexpress.com/Targets/hppd.html2026-08-24daily https://www.medchemexpress.com/Targets/NKCC.html2026-08-24daily https://www.medchemexpress.com/Targets/endoplasmic-reticulum-oxidoreductase-1-ero1.html2026-08-24daily https://www.medchemexpress.com/Targets/VD_VDR.html2026-08-24daily https://www.medchemexpress.com/Targets/Mixed%20Lineage%20Kinase.html2026-08-24daily https://www.medchemexpress.com/Targets/Porcupine.html2026-08-24daily https://www.medchemexpress.com/Targets/isotope-labeled-compounds.html2026-08-24daily https://www.medchemexpress.com/Targets/peroxidase-enzyme.html2026-08-24daily https://www.medchemexpress.com/Targets/β-glucuronidase.html2026-08-24daily https://www.medchemexpress.com/Targets/HDAC.html2026-08-24daily https://s3.medchemexpress.com/Targets/MCE-HDAC-Signaling-Pathway.pngTCR, GPCR and HDAC II interaction: Diverse agonists act through G-protein-coupled receptors (GPCRs) to activate the PKC-PKD axis, CaMK, Rho, or MHC binding to antigens stimulates TCR to activate PKD, leading to phosphorylation of class II HDACs. Phospho-HDACs dissociate from MEF2, bind 14-3-3, and are exported to the cytoplasm through a CRM1-dependent mechanism. CRM1 is inhibited by leptomycin B (LMB). Release of MEF2 from class II HDACs allows p300 to dock on MEF2 and stimulate gene expression. Dephosphorylation of class II HDACs in the cytoplasm enables reentry into the nucleus[1]. TLR: TLR signaling is initiated by ligand binding to receptors. The recruitment of TLR domain-containing adaptor protein MyD88 is repressed by HDAC6, whereas NF-κB and MTA-1 can be negatively regulated by HDAC1/2/3 and HDAC2, respectively. Acetylation by HATs enhance MKP-1 which inhibits p38-mediated inflammatory responses, while HDAC1/2/3 inhibits MKP-1 activity. HDAC1 and HDAC8 repress, whereas HDAC6 promotes, IRF function in response to viral challenge. HDAC11 inhibits IL-10 expression and HDAC1 and HDAC2 represses IFNγ-dependent activation of the CIITA transcription factor, thus affecting antigen presentation[2][3]. IRNAR: IFN-α/β induce activation of the type I IFN receptor and then bring the receptor-associated JAKs into proximity. JAK adds phosphates to the receptor. STATs bind to the phosphates and then phosphorylated by JAKs to form a dimer, leading to nuclear translocation and gene expression. HDACs positively regulate STATs and PZLF to promote antiviral responses and IFN-induced gene expression[2][3]. Cell cycle: In G1 phase, HDAC, Retinoblastoma protein (RB), E2F and polypeptide (DP) form a repressor complex. HDAC acts on surrounding chromatin, causing it to adopt a closed chromatin conformation, and transcription is repressed. Prior to the G1-S transition, phosphorylation of RB by CDKs dissociates the repressor complex. Transcription factors (TFs) gain access to their binding sites and, together with the now unmasked E2F activation domain. E2F is then free to activate transcription by contacting basal factors or by contacting histone acetyltransferases, such as CBP, that can alter chromatin structure[4]. The function of non-histone proteins is also regulated by HATs/HDACs. p53: HDAC1 impairs the function of p53. p53 is acetylated under conditions of stress or HDAC inhibition by its cofactor CREB binding protein (CBP) and the transcription of genes involved in differentiation is activated. HSP90: HSP90 is a chaperone that complexes with other chaperones, such as p23, to maintain correct conformational folding of its client proteins. HDAC6 deacetylates HSP90. Inhibition of HDAC6 would result in hyperacetylated HSP90, which would be unable to interact with its co-chaperones and properly lead to misfolded client proteins being targeted for degradation via the ubiquitin-proteasome system[5][6]. Reference:[1]. Vega RB, et al. Protein kinases C and D mediate agonist-dependent cardiac hypertrophy through nuclear export of histone deacetylase 5.Mol Cell Biol. 2004 Oct;24(19):8374-85.[2]. Shakespear MR, et al. Histone deacetylases as regulators of inflammation and immunity. Trends Immunol. 2011 Jul;32(7):335-43.[3]. Suliman BA, et al. HDACi: molecular mechanisms and therapeutic implications in the innate immune system.Immunol Cell Biol. 2012 Jan;90(1):23-32. [4]. Brehm A, et al. Retinoblastoma protein meets chromatin.Trends Biochem Sci. 1999 Apr;24(4):142-5.[5]. Butler R, et al. Histone deacetylase inhibitors as therapeutics for polyglutamine disorders.Nat Rev Neurosci. 2006 Oct;7(10):784-96[6]. Minucci S, et al. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer.Nat Rev Cancer. 2006 Jan;6(1):38-51.HDAC Signaling Pathway | MedChemExpresshttps://www.medchemexpress.com https://www.medchemexpress.com/Targets/gpr39.html2026-08-24daily https://www.medchemexpress.com/Targets/MNK.html2026-08-24daily https://www.medchemexpress.com/Targets/Lactate%20Dehydrogenase.html2026-08-24daily https://www.medchemexpress.com/Targets/Haspin%20Kinase.html2026-08-24daily https://www.medchemexpress.com/Targets/fluorescent-dye.html2026-08-24daily https://www.medchemexpress.com/Targets/e-selectin.html2026-08-24daily https://www.medchemexpress.com/Targets/tomato-spotted-wilt-virus-tswv.html2026-08-24daily https://www.medchemexpress.com/Targets/adhesion-g-protein-coupled-receptors-agpcrs.html2026-08-24daily https://www.medchemexpress.com/Targets/sdcbp.html2026-08-24daily https://www.medchemexpress.com/Targets/phosphomannose-isomerase-pmi.html2026-08-24daily https://www.medchemexpress.com/Targets/DGAT.html2026-08-24daily https://www.medchemexpress.com/Targets/Thymidylate%20Synthase.html2026-08-24daily https://www.medchemexpress.com/Targets/Carbonic%20Anhydrase.html2026-08-24daily https://www.medchemexpress.com/Targets/Bradykinin%20Receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/ebv.html2026-08-24daily https://www.medchemexpress.com/Targets/adamts.html2026-08-24daily https://www.medchemexpress.com/Targets/cryptochrome.html2026-08-24daily https://www.medchemexpress.com/Targets/acetyl-coa-synthetase.html2026-08-24daily https://www.medchemexpress.com/Targets/angptl.html2026-08-24daily https://www.medchemexpress.com/Targets/spfh-protein-superfamily.html2026-08-24daily https://www.medchemexpress.com/Targets/MMP.html2026-08-24daily https://www.medchemexpress.com/Targets/calmodulin.html2026-08-24daily https://www.medchemexpress.com/Targets/tlk.html2026-08-24daily https://www.medchemexpress.com/Targets/PERK.html2026-08-24daily https://www.medchemexpress.com/Targets/mitosis.html2026-08-24daily https://www.medchemexpress.com/Targets/RGS%20Protein.html2026-08-24daily https://www.medchemexpress.com/Targets/Angiotensin%20Receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/brk.html2026-08-24daily https://www.medchemexpress.com/Targets/SRPK.html2026-08-24daily https://www.medchemexpress.com/Targets/sFRP-1.html2026-08-24daily https://www.medchemexpress.com/Targets/succinate-receptor-1.html2026-08-24daily https://www.medchemexpress.com/Targets/p97.html2026-08-24daily https://www.medchemexpress.com/Targets/disulfidptosis.html2026-08-24daily https://www.medchemexpress.com/Targets/phostacs.html2026-08-24daily https://www.medchemexpress.com/Targets/IRAK.html2026-08-24daily https://www.medchemexpress.com/Targets/ERK.html2026-08-24daily https://www.medchemexpress.com/Targets/microsomal-triglyceride-transfer-protein-mtp.html2026-08-24daily https://www.medchemexpress.com/Targets/drug-derivative.html2026-08-24daily https://www.medchemexpress.com/Targets/hapten.html2026-08-24daily https://www.medchemexpress.com/Targets/cd28.html2026-08-24daily https://www.medchemexpress.com/Targets/flaviviridae.html2026-08-24daily https://www.medchemexpress.com/Targets/Histamine%20Receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/CRFR.html2026-08-24daily https://www.medchemexpress.com/Targets/paraptosis.html2026-08-24daily https://www.medchemexpress.com/Targets/LRRK2.html2026-08-24daily https://www.medchemexpress.com/Targets/sialyltransferase.html2026-08-24daily https://www.medchemexpress.com/Targets/Pim.html2026-08-24daily https://www.medchemexpress.com/Targets/early-2-factor-e2f.html2026-08-24daily https://www.medchemexpress.com/Targets/cd44.html2026-08-24daily https://www.medchemexpress.com/Targets/Melanocortin%20Receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/trace-amine-associated-receptor-taar.html2026-08-24daily https://www.medchemexpress.com/Targets/Trk%20Receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/ask1.html2026-08-24daily https://www.medchemexpress.com/Targets/choline-kinase.html2026-08-24daily https://www.medchemexpress.com/Targets/3β-hsd.html2026-08-24daily https://www.medchemexpress.com/Targets/dgk.html2026-08-24daily https://www.medchemexpress.com/Targets/Kinesin.html2026-08-24daily https://www.medchemexpress.com/Targets/Adrenergic%20Receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/Fungal.html2026-08-24daily https://www.medchemexpress.com/Targets/radionuclide-drug-conjugates-rdcs.html2026-08-24daily https://www.medchemexpress.com/Targets/stk33.html2026-08-24daily https://www.medchemexpress.com/Targets/nek.html2026-08-24daily https://www.medchemexpress.com/Targets/mitochondrial-metabolism.html2026-08-24daily https://www.medchemexpress.com/Targets/CFTR.html2026-08-24daily https://www.medchemexpress.com/Targets/hydroxycarboxylic-acid-receptor-hcar.html2026-08-24daily https://www.medchemexpress.com/Targets/o-glcnac-transferase.html2026-08-24daily https://www.medchemexpress.com/Targets/FLT3.html2026-08-24daily https://www.medchemexpress.com/Targets/transglutaminase.html2026-08-24daily https://www.medchemexpress.com/Targets/Tryptophan%20Hydroxylase.html2026-08-24daily https://www.medchemexpress.com/Targets/E3%20Ligase%20Ligand-Linker%20Conjugate.html2026-08-24daily https://www.medchemexpress.com/Targets/cp.html2026-08-24daily https://www.medchemexpress.com/Targets/Hippo%20(MST).html2026-08-24daily https://www.medchemexpress.com/Targets/γ-secretase.html2026-08-24daily https://www.medchemexpress.com/Targets/reactive-oxygen-species.html2026-08-24daily https://www.medchemexpress.com/Targets/factor-viii.html2026-08-24daily https://www.medchemexpress.com/Targets/sult.html2026-08-24daily https://www.medchemexpress.com/Targets/BCRP.html2026-08-24daily https://www.medchemexpress.com/Targets/phosphoglycerate-kinase-pgk.html2026-08-24daily https://www.medchemexpress.com/Targets/Pyruvate%20Dehydrogenase.html2026-08-24daily https://www.medchemexpress.com/Targets/Farnesyl%20Transferase.html2026-08-24daily https://www.medchemexpress.com/Targets/Serotonin%20Transporter.html2026-08-24daily https://www.medchemexpress.com/Targets/CRAC%20Channel.html2026-08-24daily https://www.medchemexpress.com/Targets/hyt.html2026-08-24daily https://www.medchemexpress.com/Targets/byetac.html2026-08-24daily https://www.medchemexpress.com/Targets/Isocitrate%20Dehydrogenase%20(IDH).html2026-08-24daily https://www.medchemexpress.com/Targets/Influenza%20Virus.html2026-08-24daily https://www.medchemexpress.com/Targets/glyoxalase-glo.html2026-08-24daily https://www.medchemexpress.com/Targets/PROTAC-linker%20Conjugate%20for%20PAC.html2026-08-24daily https://www.medchemexpress.com/Targets/TSH%20Receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/proteolytic-enzyme.html2026-08-24daily https://www.medchemexpress.com/Targets/FGFR.html2026-08-24daily https://www.medchemexpress.com/Targets/Caspase.html2026-08-24daily https://s3.medchemexpress.com/Targets/MCE-Caspase-Signaling-Pathway.pngUpon binding to their cognate ligand, death receptors such as Fas and TRAILR can activate initiator Caspases (Pro-caspase 8 and Pro-caspase 10) through dimerization mediated by adaptor proteins such as FADD and TRADD. Active Caspase 8 and Caspase 10 then cleave and activate the effector Caspase 3, 6 and 7, leading to apoptosis. ROS/DNA damage and ER stress trigger Caspase 2 activation. Active Caspase 2 cleaves and activates Caspase 3 and initiates apoptosis directly. Caspase 2, 8 and 10 can also cleave Bid, stimulate mitochondrial outer membrane permeabilization (MOMP) and initiate the intrinsic apoptotic pathway. Following MOMP, mitochondrial intermembrane space proteins such as Smac and Cytochrome C are released into the cytosol. Cytochrome C interacts with Apaf-1, triggering apoptosome assembly, which activates Caspase 9. Active Caspase 9, in turn, activates Caspase 3, 6 and 7, leading to apoptosis. Mitochondrial release of Smac facilitates apoptosis by blocking the inhibitor of apoptosis (IAP) proteins. Following the binding of TNF to TNFR1, TNFR1 binds to TRADD, which recruits RIPK1, TRAF2/5 and cIAP1/2 to form TNFR1 signaling complex I. Formation of the complex IIa and complex IIb is initiated either by RIPK1 deubiquitylation mediated by CYLD or by RIPK1 non-ubiquitylation due to depletion of cIAPs. The Pro-caspase 8 homodimer in complex IIa and complex IIb generates active Caspase 8. This active Caspase 8 in the cytosol then carries out cleavage reactions to activate downstream executioner caspases and thus induce classical apoptosis[1][2]. Reference:[1]. Thomas C, et al. Caspases in retinal ganglion cell death and axon regeneration. Cell Death Discovery volume 3, Article number: 17032 (2017).[2]. Brenner D, et al. Regulation of tumour necrosis factor signalling: live or let die. Nat Rev Immunol. 2015 Jun;15(6):362-74.Caspase Signaling Pathway | MedChemExpresshttps://www.medchemexpress.com https://www.medchemexpress.com/Targets/β-catenin.html2026-08-24daily https://www.medchemexpress.com/Targets/s-adenosylhomocysteine-hydrolase-sahh.html2026-08-24daily https://www.medchemexpress.com/Targets/ghr.html2026-08-24daily https://www.medchemexpress.com/Targets/IKK.html2026-08-24daily https://www.medchemexpress.com/Targets/cadherin.html2026-08-24daily https://www.medchemexpress.com/Targets/neuropeptide-ff-receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/Mps1.html2026-08-24daily https://www.medchemexpress.com/Targets/hsp70tac.html2026-08-24daily https://www.medchemexpress.com/Targets/fc-receptor-fcr.html2026-08-24daily https://www.medchemexpress.com/Targets/Na+_K+%20ATPase.html2026-08-24daily https://www.medchemexpress.com/Targets/STING.html2026-08-24daily https://www.medchemexpress.com/Targets/Adiponectin%20Receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/ROS.html2026-08-24daily https://www.medchemexpress.com/Targets/branched-chain-amino-acid-transaminase-bcat.html2026-08-24daily https://www.medchemexpress.com/Targets/arf-family-gtpase.html2026-08-24daily https://www.medchemexpress.com/Targets/nAChR.html2026-08-24daily https://www.medchemexpress.com/Targets/beclin1.html2026-08-24daily https://www.medchemexpress.com/Targets/constitutive-androstane-receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/kallikrein.html2026-08-24daily https://www.medchemexpress.com/Targets/vzv.html2026-08-24daily https://www.medchemexpress.com/Targets/Androgen%20Receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/ferrochelatase.html2026-08-24daily https://www.medchemexpress.com/Targets/Hedgehog.html2026-08-24daily https://www.medchemexpress.com/Targets/cyclin-g-associated-kinase-gak.html2026-08-24daily https://www.medchemexpress.com/Targets/annexin-a.html2026-08-24daily https://www.medchemexpress.com/Targets/cd6.html2026-08-24daily https://www.medchemexpress.com/Targets/IFNAR.html2026-08-24daily https://www.medchemexpress.com/Targets/VDAC.html2026-08-24daily https://www.medchemexpress.com/Targets/transferrin-receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/trem-receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/cd276-b7-h3.html2026-08-24daily https://www.medchemexpress.com/Targets/PKC.html2026-08-24daily https://www.medchemexpress.com/Targets/Metabolite.html2026-08-24daily https://www.medchemexpress.com/Targets/pask-stk37.html2026-08-24daily https://www.medchemexpress.com/Targets/nectin-4.html2026-08-24daily https://www.medchemexpress.com/Targets/MALT1.html2026-08-24daily https://www.medchemexpress.com/Targets/amine-n-methyltransferase.html2026-08-24daily https://www.medchemexpress.com/Targets/epoxide-hydrolase.html2026-08-24daily https://www.medchemexpress.com/Targets/dihydroorotate-dehydrogenase.html2026-08-24daily https://www.medchemexpress.com/Targets/p62.html2026-08-24daily https://www.medchemexpress.com/Targets/Bacterial.html2026-08-24daily https://www.medchemexpress.com/Targets/nucleoside-transporters.html2026-08-24daily https://www.medchemexpress.com/Targets/LIM%20Kinase%20(LIMK).html2026-08-24daily https://www.medchemexpress.com/Targets/TNF-alpha.html2026-08-24daily https://s3.medchemexpress.com/Targets/MCE-TNF-Receptor-Signaling-Pathway.pngFollowing the binding of TNF to TNF receptors, TNFR1 binds to TRADD, which recruits RIPK1, TRAF2/5 and cIAP1/2 to form TNFR1 signaling complex I; TNFR2 binds to TRAF1/2 directly to recruit cIAP1/2. Both cIAP1 and cIAP2 are E3 ubiquitin ligases that add K63 linked polyubiquitin chains to RIPK1 and other components of the signaling complex. The ubiquitin ligase activity of the cIAPs is needed to recruit the LUBAC, which adds M1 linked linear polyubiquitin chains to RIPK1. K63 polyubiquitylated RIPK1 recruits TAB2, TAB3 and TAK1, which activate signaling mediated by JNK and p38, as well as the IκB kinase complex. The IKK complex then activates NF-κB signaling, which leads to the transcription of anti-apoptotic factors-such as FLIP and Bcl-XL-that promote cell survival. The formation of TNFR1 complex IIa and complex IIb depends on non-ubiquitylated RIPK1. For the formation of complex IIa, ubiquitylated RIPK1 in complex I is deubiquitylated by CYLD. This deubiquitylated RIPK1 dissociates from the membrane-bound complex and moves into the cytosol, where it interacts with TRADD, FADD, Pro-caspase 8 and FLIPL to form complex IIa. By contrast, complex IIb is formed when the RIPK1 in complex I is not ubiquitylated owing to conditions that have resulted in the depletion of cIAPs, which normally ubiquitylate RIPK1. This non-ubiquitylated RIPK1 dissociates from complex I, moves into the cytosol, and assembles with FADD, Pro-caspase 8, FLIPL and RIPK3 (but not TRADD) to form complex IIb. For either complex IIa or complex IIb to prevent necroptosis, both RIPK1 and RIPK3 must be inactivated by the cleavage activity of the Pro-caspase 8-FLIPL heterodimer or fully activated caspase 8. The Pro-caspase 8 homodimer generates active Caspase 8, which is released from complex IIa and complex IIb. This active Caspase 8 then carries out cleavage reactions to activate downstream executioner caspases and thus induce classical apoptosis. Formation of the complex IIc (necrosome) is initiated either by RIPK1 deubiquitylation mediated by CYLD or by RIPK1 non-ubiquitylation due to depletion of cIAPs, similar to complex IIa and complex IIb formation. RIPK1 recruits numerous RIPK3 molecules. They come together to form amyloid microfilaments called necrosomes. Activated RIPK3 phosphorylates and recruits MLKL, eventually leading to the formation of a supramolecular protein complex at the plasma membrane and necroptosis [1][2]. Reference:[1]. Brenner D, et al. Regulation of tumour necrosis factor signalling: live or let die.Nat Rev Immunol. 2015 Jun;15(6):362-74. [2]. Conrad M, et al. Regulated necrosis: disease relevance and therapeutic opportunities.Nat Rev Drug Discov. 2016 May;15(5):348-66. TNF Receptor Signaling Pathway | MedChemExpresshttps://www.medchemexpress.com https://www.medchemexpress.com/Targets/lilrb.html2026-08-24daily https://www.medchemexpress.com/Targets/SGK.html2026-08-24daily https://www.medchemexpress.com/Targets/factor-xi.html2026-08-24daily https://www.medchemexpress.com/Targets/marcks.html2026-08-24daily https://www.medchemexpress.com/Targets/yb-1.html2026-08-24daily https://www.medchemexpress.com/Targets/PDK-1.html2026-08-24daily https://www.medchemexpress.com/Targets/Arp2_3%20Complex.html2026-08-24daily https://www.medchemexpress.com/Targets/ROR.html2026-08-24daily https://www.medchemexpress.com/Targets/fkbp.html2026-08-24daily https://www.medchemexpress.com/Targets/ketohexokinase.html2026-08-24daily https://www.medchemexpress.com/Targets/RAR_RXR.html2026-08-24daily https://www.medchemexpress.com/Targets/aak1.html2026-08-24daily https://www.medchemexpress.com/Targets/Syk.html2026-08-24daily https://www.medchemexpress.com/Targets/tissue-factor-pathway-inhibitor-tfpi.html2026-08-24daily https://www.medchemexpress.com/Targets/sr.html2026-08-24daily https://www.medchemexpress.com/Targets/formyl-peptide-receptor-fpr.html2026-08-24daily https://www.medchemexpress.com/Targets/bcl6.html2026-08-24daily https://www.medchemexpress.com/Targets/wnk-kinase.html2026-08-24daily https://www.medchemexpress.com/Targets/urease.html2026-08-24daily https://www.medchemexpress.com/Targets/environmental-contaminants.html2026-08-24daily https://www.medchemexpress.com/Targets/microtubule-associated-serine-threonine-kinase-mast.html2026-08-24daily https://www.medchemexpress.com/Targets/na-h-exchanger-nhe.html2026-08-24daily https://www.medchemexpress.com/Targets/beta-lactamase.html2026-08-24daily https://www.medchemexpress.com/Targets/microphthalmia-associated-transcription-factor-mitf.html2026-08-24daily https://www.medchemexpress.com/Targets/HCN%20Channel.html2026-08-24daily https://www.medchemexpress.com/Targets/foxa.html2026-08-24daily https://www.medchemexpress.com/Targets/Gutathione%20S-transferase.html2026-08-24daily https://www.medchemexpress.com/Targets/biochemical-assay-reagents.html2026-08-24daily https://www.medchemexpress.com/Targets/Bombesin%20Receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/folate-receptor-fr.html2026-08-24daily https://www.medchemexpress.com/Targets/MDM-2_p53.html2026-08-24daily https://s3.medchemexpress.com/Targets/MCE-MDM-2-p53-Signaling-Pathway.pngp53 is at the centre of biological interactions that translates stress signals into cell cycle arrest or apoptosis. Upstream signaling to p53 increases its level and activates its function as a transcription factor in response to a wide variety of stresses, whereas downstream components execute the appropriate cellular response. Cell Stress: p53 induction by acute DNA damage begins when DNA double-strand breaks trigger activation of ATM, a kinase that phosphorylates the CHK2 kinase, or when stalled or collapsed DNA replication forks recruit ATR, which phosphorylates CHK1. p53 is a substrate for both the ATM and ATR kinases, as well as for CHK1 and CHK2, which coordinately phosphorylate p53 to promote its stabilization. These phosphorylation events are important for p53 stabilization, as some of the modifications disrupt the interaction between p53 and its negative regulators MDM2 and MDM4. MDM2 and MDM4 bind to the transcriptional activation domains of p53, thereby inhibiting p53 transactivation function, and MDM2 has additional activity as an E3 ubiquitin ligase that causes proteasome-mediated degradation of p53. Phosphorylation also allows the interaction of p53 with transcriptional cofactors, which is ultimately important for activation of target genes and for responses such as cell cycle arrest, DNA repair, apoptosis and senescence. Non-receptor tyrosine kinase c-Abl can also be activated by DNA damage. Then the JNK/p38 is activated and leads to p53 activation[1][2]. Oncogenic signaling: The response to oncogene activation depends on the binding of ARF to MDM2. ARF is normally expressed at low levels in cells. Inappropriately increased E2F or Myc signals, stemming from oncogene activation, leads to the increased expression of ARF, which inhibits MDM2 by blocking its E3 ubiquitin ligase activity, uncoupling the p53-MDM2 interaction, thereby segregating it from nucleoplasmic p53[3]. The PI3K-Akt pathway activates MDM2 and increases the ubiquitination of p53. Reference:[1]. Chène P, et al. Inhibiting the p53-MDM2 interaction: an important target for cancer therapy. Nat Rev Cancer. 2003 Feb;3(2):102-9.[2]. Brown CJ, et al. Awakening guardian angels: drugging the p53 pathway. Nat Rev Cancer. 2009 Dec;9(12):862-73. [3]. Polager S, et al. p53 and E2f: partners in life and death. Nat Rev Cancer. 2009 Oct;9(10):738-48. doi: 10.1038/nrc2718.MDM-2/p53 Signaling Pathway | MedChemExpresshttps://www.medchemexpress.com https://www.medchemexpress.com/Targets/Ack1.html2026-08-24daily https://www.medchemexpress.com/Targets/Prostaglandin%20Receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/RAD51.html2026-08-24daily https://www.medchemexpress.com/Targets/Bcr-Abl.html2026-08-24daily https://www.medchemexpress.com/Targets/reference-standards.html2026-08-24daily https://www.medchemexpress.com/Targets/DNA%20Stain.html2026-08-24daily https://www.medchemexpress.com/Targets/Leukotriene%20Receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/acsl-family.html2026-08-24daily https://www.medchemexpress.com/Targets/MyD88.html2026-08-24daily https://www.medchemexpress.com/Targets/Cathepsin.html2026-08-24daily https://www.medchemexpress.com/Targets/rio-kinase.html2026-08-24daily https://www.medchemexpress.com/Targets/snrk.html2026-08-24daily https://www.medchemexpress.com/Targets/Oxytocin%20Receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/olig2.html2026-08-24daily https://www.medchemexpress.com/Targets/Deubiquitinase.html2026-08-24daily https://www.medchemexpress.com/Targets/Ligand%20for%20E3%20Ligase.html2026-08-24daily https://www.medchemexpress.com/Targets/Topoisomerase.html2026-08-24daily https://www.medchemexpress.com/Targets/arrestin.html2026-08-24daily https://www.medchemexpress.com/Targets/fat-mass-and-obesity-associated-protein-fto.html2026-08-24daily https://www.medchemexpress.com/Targets/EBI2_GPR183.html2026-08-24daily https://www.medchemexpress.com/Targets/PPAR.html2026-08-24daily https://www.medchemexpress.com/Targets/HIV.html2026-08-24daily https://www.medchemexpress.com/Targets/pkg.html2026-08-24daily https://www.medchemexpress.com/Targets/lipidosome.html2026-08-24daily https://www.medchemexpress.com/Targets/E1_E2_E3%20Enzyme.html2026-08-24daily https://www.medchemexpress.com/Targets/Proteasome.html2026-08-24daily https://www.medchemexpress.com/Targets/c-Kit.html2026-08-24daily https://www.medchemexpress.com/Targets/succinate-dehydrogenase.html2026-08-24daily https://www.medchemexpress.com/Targets/ythdf.html2026-08-24daily https://www.medchemexpress.com/Targets/Apoptosis.html2026-08-24daily https://www.medchemexpress.com/Targets/eukaryotic-release-factor-erf.html2026-08-24daily https://www.medchemexpress.com/Targets/Toll-like%20Receptor%20(TLR).html2026-08-24daily https://www.medchemexpress.com/Targets/cyclic-gmp-amp-synthase.html2026-08-24daily https://www.medchemexpress.com/Targets/tmprss6.html2026-08-24daily https://www.medchemexpress.com/Targets/huntingtin.html2026-08-24daily https://www.medchemexpress.com/Targets/amino-acid-derivatives.html2026-08-24daily https://www.medchemexpress.com/Targets/prokineticin-receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/JAK.html2026-08-24daily https://www.medchemexpress.com/Targets/lipocalin-family.html2026-08-24daily https://www.medchemexpress.com/Targets/Indoleamine%202,3-Dioxygenase%20(IDO).html2026-08-24daily https://www.medchemexpress.com/Targets/shp1.html2026-08-24daily https://www.medchemexpress.com/Targets/hemoglobin.html2026-08-24daily https://www.medchemexpress.com/Targets/gpr52.html2026-08-24daily https://www.medchemexpress.com/Targets/MAGL.html2026-08-24daily https://www.medchemexpress.com/Targets/hoxa.html2026-08-24daily https://www.medchemexpress.com/Targets/Drug%20Metabolite.html2026-08-24daily https://www.medchemexpress.com/Targets/amylases.html2026-08-24daily https://www.medchemexpress.com/Targets/Phosphodiesterase%20(PDE).html2026-08-24daily https://www.medchemexpress.com/Targets/Sigma%20Receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/sex-pheromone.html2026-08-24daily https://www.medchemexpress.com/Targets/Telomerase.html2026-08-24daily https://www.medchemexpress.com/Targets/FAK.html2026-08-24daily https://www.medchemexpress.com/Targets/MEK.html2026-08-24daily https://www.medchemexpress.com/Targets/orphan-nuclear-receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/Survivin.html2026-08-24daily https://www.medchemexpress.com/Targets/Carboxypeptidase.html2026-08-24daily https://www.medchemexpress.com/Targets/Wee1.html2026-08-24daily https://www.medchemexpress.com/Targets/Chloride%20Channel.html2026-08-24daily https://www.medchemexpress.com/Targets/glucosylceramide-synthase-gcs.html2026-08-24daily https://www.medchemexpress.com/Targets/Neurotensin%20Receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/PROTAC.html2026-08-24daily https://www.medchemexpress.com/Targets/Nucleoside%20Antimetabolite_Analog.html2026-08-24daily https://www.medchemexpress.com/Targets/c-Fms.html2026-08-24daily https://www.medchemexpress.com/Targets/Somatostatin%20Receptor.html2026-08-24daily https://www.medchemexpress.com/Targets/furin.html2026-08-24daily