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Tyrosine-protein kinase Lyn

Definition:

Non-receptor tyrosine-protein kinase that transmits signals from cell surface receptors and plays an important role in the regulation of innate and adaptive immune responses, hematopoiesis, responses to growth factors and cytokines, integrin signaling, but also responses to DNA damage and genotoxic agents. Functions primarily as negative regulator, but can also function as activator, depending on the context. Required for the initiation of the B-cell response, but also for its down-regulation and termination. Plays an important role in the regulation of B-cell differentiation, proliferation, survival and apoptosis, and is important for immune self-tolerance. Acts downstream of several immune receptors, including the B-cell receptor, CD79A, CD79B, CD5, CD19, CD22, FCER1, FCGR2, FCGR1A, TLR2 and TLR4. Plays a role in the inflammatory response to bacterial lipopolysaccharide. Mediates the responses to cytokines and growth factors in hematopoietic progenitors, platelets, erythrocytes, and in mature myeloid cells, such as dendritic cells, neutrophils and eosinophils. Acts downstream of EPOR, KIT, MPL, the chemokine receptor CXCR4, as well as the receptors for IL3, IL5 and CSF2. Plays an important role in integrin signaling. Regulates cell proliferation, survival, differentiation, migration, adhesion, degranulation, and cytokine release. Down-regulates signaling pathways by phosphorylation of immunoreceptor tyrosine-based inhibitory motifs (ITIM), that then serve as binding sites for phosphatases, such as PTPN6/SHP-1, PTPN11/SHP-2 and INPP5D/SHIP-1, that modulate signaling by dephosphorylation of kinases and their substrates. Phosphorylates LIME1 in response to CD22 activation. Phosphorylates BTK, CBL, CD5, CD19, CD72, CD79A, CD79B, CSF2RB, DOK1, HCLS1, LILRB3/PIR-B, MS4A2/FCER1B, SYK and TEC. Promotes phosphorylation of SIRPA, PTPN6/SHP-1, PTPN11/SHP-2 and INPP5D/SHIP-1. Mediates phosphorylation of the BCR-ABL fusion protein. Required for rapid phosphorylation of FER in response to FCER1 activation. Mediates KIT phosphorylation. Acts as an effector of EPOR (erythropoietin receptor) in controlling KIT expression and may play a role in erythroid differentiation during the switch between proliferation and maturation. Depending on the context, activates or inhibits several signaling cascades. Regulates phosphatidylinositol 3-kinase activity and AKT1 activation. Regulates activation of the MAP kinase signaling cascade, including activation of MAP2K1/MEK1, MAPK1/ERK2, MAPK3/ERK1, MAPK8/JNK1 and MAPK9/JNK2. Mediates activation of STAT5A and/or STAT5B. Phosphorylates LPXN on 'Tyr-72'. Kinase activity facilitates TLR4-TLR6 heterodimerization and signal initiation. Phosphorylates SCIMP on 'Tyr-107'; this enhances binding of SCIMP to TLR4, promoting the phosphorylation of TLR4, and a selective cytokine response to lipopolysaccharide in macrophages (By similarity). Phosphorylates CLNK (By similarity). Phosphorylates BCAR1/CAS and NEDD9/HEF1.

References:

[1]. Cédric Dos Santos, et al. A critical role for Lyn in acute myeloid leukemia. Blood. 2008 Feb 15;111(4):2269-79. [Content Brief]

[2]. Valerie Chew, et al. Leupaxin negatively regulates B cell receptor signaling. J Biol Chem. 2007 Sep 14;282(37):27181-27191. [Content Brief]

[3]. Patrizia Scapini, et al. Multiple roles of Lyn kinase in myeloid cell signaling and function. Immunol Rev. 2009 Mar;228(1):23-40. [Content Brief]

[4]. Juan Zhang, et al. TOM1L1 is a Lyn substrate involved in FcepsilonRI signaling in mast cells. J Biol Chem. 2007 Dec 28;282(52):37669-77. [Content Brief]

[5]. Sebastien Tauzin, et al. Oncogenic association of the Cbp/PAG adaptor protein with the Lyn tyrosine kinase in human B-NHL rafts. Blood. 2008 Feb 15;111(4):2310-20. [Content Brief]

[6]. Cameron R Stewart, et al. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol. 2010 Feb;11(2):155-61. [Content Brief]

[7]. K Yoshida, et al. Functional interaction between SHPTP1 and the Lyn tyrosine kinase in the apoptotic response to DNA damage. J Biol Chem. 1999 Dec 3;274(49):34663-8. [Content Brief]

[8]. C M Roifman, et al. CD19 is a substrate of the antigen receptor-associated protein tyrosine kinase in human B cells. Biochem Biophys Res Commun. 1993 Jul 15;194(1):222-5. [Content Brief]

[9]. K Yoshida, et al. Role for Lyn tyrosine kinase as a regulator of stress-activated protein kinase activity in response to DNA damage. Mol Cell Biol. 2000 Aug;20(15):5370-80. [Content Brief]

[10]. B O'Laughlin-Bunner, et al. Lyn is required for normal stem cell factor-induced proliferation and chemotaxis of primary hematopoietic cells. Blood. 2001 Jul 15;98(2):343-50. [Content Brief]

[11]. Yuji Nakata, et al. Integrin inhibition through Lyn-dependent cross talk from CXCR4 chemokine receptors in normal human CD34+ marrow cells. Blood. 2006 Jun 1;107(11):4234-9. [Content Brief]

[12]. Ji Wu, et al. Association between imatinib-resistant BCR-ABL mutation-negative leukemia and persistent activation of LYN kinase. J Natl Cancer Inst. 2008 Jul 2;100(13):926-39. [Content Brief]

[13]. Ji Wu, et al. Lyn regulates BCR-ABL and Gab2 tyrosine phosphorylation and c-Cbl protein stability in imatinib-resistant chronic myelogenous leukemia cells. Blood. 2008 Apr 1;111(7):3821-9. [Content Brief]

[14]. Mobeen Malik, et al. Monocyte migration and LFA-1-mediated attachment to brain microvascular endothelia is regulated by SDF-1 alpha through Lyn kinase. J Immunol. 2008 Oct 1;181(7):4632-7. [Content Brief]

[15]. A V Grishin, et al. Interaction between growth arrest-DNA damage protein 34 and Src kinase Lyn negatively regulates genotoxic apoptosis. Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10172-7. [Content Brief]

[16]. Brian J Lannutti, et al. Lyn tyrosine kinase regulates thrombopoietin-induced proliferation of hematopoietic cell lines and primary megakaryocytic progenitors. Blood. 2004 May 15;103(10):3736-43. [Content Brief]

[17]. Xiquan Liang, et al. Phosphatidylinositol 3-kinase and Src family kinases are required for phosphorylation and membrane recruitment of Dok-1 in c-Kit signaling. J Biol Chem. 2002 Apr 19;277(16):13732-8. [Content Brief]

[18]. B S Gaul, et al. Substrate recognition by the Lyn protein-tyrosine kinase. NMR structure of the immunoreceptor tyrosine-based activation motif signaling region of the B cell antigen receptor. J Biol Chem. 2000 May 26;275(21):16174-82. [Content Brief]

[19]. S N Manié, et al. Involvement of p130(Cas) and p105(HEF1), a novel Cas-like docking protein, in a cytoskeleton-dependent signaling pathway initiated by ligation of integrin or antigen receptor on human B cells. J Biol Chem. 1997 Feb 14;272(7):4230-6. [Content Brief]

[20]. Anna Maria Brunati, et al. Thrombin-induced tyrosine phosphorylation of HS1 in human platelets is sequentially catalyzed by Syk and Lyn tyrosine kinases and associated with the cellular migration of the protein. J Biol Chem. 2005 Jun 3;280(22):21029-35. [Content Brief]

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