Serine/threonine-protein kinase PAK 1

Definition:

Protein kinase involved in intracellular signaling pathways downstream of integrins and receptor-type kinases that plays an important role in cytoskeleton dynamics, in cell adhesion, migration, proliferation, apoptosis, mitosis, and in vesicle-mediated transport processes. Can directly phosphorylate BAD and protects cells against apoptosis. Activated by interaction with CDC42 and RAC1. Functions as GTPase effector that links the Rho-related GTPases CDC42 and RAC1 to the JNK MAP kinase pathway. Phosphorylates and activates MAP2K1, and thereby mediates activation of downstream MAP kinases. Involved in the reorganization of the actin cytoskeleton, actin stress fibers and of focal adhesion complexes. Phosphorylates the tubulin chaperone TBCB and thereby plays a role in the regulation of microtubule biogenesis and organization of the tubulin cytoskeleton. Plays a role in the regulation of insulin secretion in response to elevated glucose levels. Part of a ternary complex that contains PAK1, DVL1 and MUSK that is important for MUSK-dependent regulation of AChR clustering during the formation of the neuromuscular junction (NMJ). Activity is inhibited in cells undergoing apoptosis, potentially due to binding of CDC2L1 and CDC2L2. Phosphorylates MYL9/MLC2. Phosphorylates RAF1 at 'Ser-338' and 'Ser-339' resulting in: activation of RAF1, stimulation of RAF1 translocation to mitochondria, phosphorylation of BAD by RAF1, and RAF1 binding to BCL2. Phosphorylates SNAI1 at 'Ser-246' promoting its transcriptional repressor activity by increasing its accumulation in the nucleus. In podocytes, promotes NR3C2 nuclear localization. Required for atypical chemokine receptor ACKR2-induced phosphorylation of LIMK1 and cofilin (CFL1) and for the up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. In synapses, seems to mediate the regulation of F-actin cluster formation performed by SHANK3, maybe through CFL1 phosphorylation and inactivation. Plays a role in RUFY3-mediated facilitating gastric cancer cells migration and invasion. In response to DNA damage, phosphorylates MORC2 which activates its ATPase activity and facilitates chromatin remodeling. In neurons, plays a crucial role in regulating GABA(A) receptor synaptic stability and hence GABAergic inhibitory synaptic transmission through its role in F-actin stabilization (By similarity). In hippocampal neurons, necessary for the formation of dendritic spines and excitatory synapses; this function is dependent on kinase activity and may be exerted by the regulation of actomyosin contractility through the phosphorylation of myosin II regulatory light chain (MLC) (By similarity). Along with GIT1, positively regulates microtubule nucleation during interphase.

References:

[1]. Mark W Mayhew, et al. Identification of phosphorylation sites in betaPIX and PAK1. J Cell Sci. 2007 Nov 15;120(Pt 22):3911-8. [Content Brief]

[2]. J L Brown, et al. Human Ste20 homologue hPAK1 links GTPases to the JNK MAP kinase pathway. Curr Biol. 1996 May 1;6(5):598-605. [Content Brief]

[3]. G Wang, et al. PAK1 regulates RUFY3-mediated gastric cancer cell migration and invasion. Cell Death Dis. 2015 Mar 12;6(3):e1682. [Content Brief]

[4]. M A Sells, et al. Human p21-activated kinase (Pak1) regulates actin organization in mammalian cells. Curr Biol. 1997 Mar 1;7(3):202-10. [Content Brief]

[5]. Guo-Lei Zhou, et al. Akt phosphorylation of serine 21 on Pak1 modulates Nck binding and cell migration. Mol Cell Biol. 2003 Nov;23(22):8058-69. [Content Brief]

[6]. Jill K Slack-Davis, et al. PAK1 phosphorylation of MEK1 regulates fibronectin-stimulated MAPK activation. J Cell Biol. 2003 Jul 21;162(2):281-91. [Content Brief]

[7]. Leah Rider, et al. JAK2 tyrosine kinase phosphorylates PAK1 and regulates PAK1 activity and functions. J Biol Chem. 2007 Oct 19;282(42):30985-96. [Content Brief]

[8]. Hua Zhou, et al. Integrin engagement differentially modulates epithelial cell motility by RhoA/ROCK and PAK1. J Biol Chem. 2005 Mar 18;280(11):10624-35. [Content Brief]

[9]. Ratna K Vadlamudi, et al. p21-activated kinase 1 regulates microtubule dynamics by phosphorylating tubulin cofactor B. Mol Cell Biol. 2005 May;25(9):3726-36. [Content Brief]

[10]. E Manser, et al. Expression of constitutively active alpha-PAK reveals effects of the kinase on actin and focal complexes. Mol Cell Biol. 1997 Mar;17(3):1129-43. [Content Brief]

[11]. Mengwei Zang, et al. Interaction between active Pak1 and Raf-1 is necessary for phosphorylation and activation of Raf-1. J Biol Chem. 2002 Feb 8;277(6):4395-405. [Content Brief]

[12]. Markéta Černohorská, et al. GIT1/βPIX signaling proteins and PAK1 kinase regulate microtubule nucleation. Biochim Biophys Acta. 2016 Jun;1863(6 Pt A):1282-97. [Content Brief]

[13]. Frederike L Harms, et al. Activating Mutations in PAK1, Encoding p21-Activated Kinase 1, Cause a Neurodevelopmental Disorder. Am J Hum Genet. 2018 Oct 4;103(4):579-591. [Content Brief]

[14]. Da-Qiang Li, et al. MORC2 signaling integrates phosphorylation-dependent, ATPase-coupled chromatin remodeling during the DNA damage response. Cell Rep. 2012 Dec 27;2(6):1657-69. [Content Brief]

[15]. F T Zenke, et al. Identification of a central phosphorylation site in p21-activated kinase regulating autoinhibition and kinase activity. J Biol Chem. 1999 Nov 12;274(46):32565-73. [Content Brief]

[16]. Ri-ichiroh Manabe, et al. GIT1 functions in a motile, multi-molecular signaling complex that regulates protrusive activity and cell migration. J Cell Sci. 2002 Apr 1;115(Pt 7):1497-510. [Content Brief]

[17]. Z S Zhao, et al. A conserved negative regulatory region in alphaPAK: inhibition of PAK kinases reveals their morphological roles downstream of Cdc42 and Rac1. Mol Cell Biol. 1998 Apr;18(4):2153-63. [Content Brief]

[18]. Zhibo Yang, et al. Pak1 phosphorylation of snail, a master regulator of epithelial-to-mesenchyme transition, modulates snail's subcellular localization and functions. Cancer Res. 2005 Apr 15;65(8):3179-84. [Content Brief]

[19]. Elena M Borroni, et al. β-arrestin-dependent activation of the cofilin pathway is required for the scavenging activity of the atypical chemokine receptor D6. Sci Signal. 2013 Apr 30;6(273):ra30.1-11, S1-3. [Content Brief]

[20]. Jia Nie, et al. Synapses of amphids defective (SAD-A) kinase promotes glucose-stimulated insulin secretion through activation of p21-activated kinase (PAK1) in pancreatic β-Cells. J Biol Chem. 2012 Jul 27;287(31):26435-44. [Content Brief]

[21]. She Chen, et al. The C-terminal kinase domain of the p34cdc2-related PITSLRE protein kinase (p110C) associates with p21-activated kinase 1 and inhibits its activity during anoikis. J Biol Chem. 2003 May 30;278(22):20029-36. [Content Brief]

Biomedical Dictionary

The Biomedical Dictionary is a comprehensive and professional collection of biological academic terms and subject datas. All explanations are supported by authoritative books or high impact factor literatures, and you can acquire accurate explanations of the biomedical terms you want to know.

A B C D E F G H I J K L M N O P Q R S T U V W X Y Z #

Name
Email *

	Sorry, but the email address you supplied was invalid.