9d4y

Structural highlights

Function

PAK1_HUMAN 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.^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15]}

References

1. ↑ Brown JL, Stowers L, Baer M, Trejo J, Coughlin S, Chant J. Human Ste20 homologue hPAK1 links GTPases to the JNK MAP kinase pathway. Curr Biol. 1996 May 1;6(5):598-605. PMID:8805275
2. ↑ Sells MA, Knaus UG, Bagrodia S, Ambrose DM, Bokoch GM, Chernoff J. Human p21-activated kinase (Pak1) regulates actin organization in mammalian cells. Curr Biol. 1997 Mar 1;7(3):202-10. PMID:9395435
3. ↑ Manser E, Huang HY, Loo TH, Chen XQ, Dong JM, Leung T, Lim L. 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. PMID:9032240
4. ↑ Zhao ZS, Manser E, Chen XQ, Chong C, Leung T, Lim L. 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. PMID:9528787
5. ↑ Zenke FT, King CC, Bohl BP, Bokoch GM. 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. PMID:10551809
6. ↑ Zang M, Hayne C, Luo Z. 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. Epub 2001 Nov 30. PMID:11733498 doi:10.1074/jbc.M110000200
7. ↑ Chen S, Yin X, Zhu X, Yan J, Ji S, Chen C, Cai M, Zhang S, Zong H, Hu Y, Yuan Z, Shen Z, Gu J. 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. Epub 2003 Mar 6. PMID:12624090 doi:10.1074/jbc.M300818200
8. ↑ Slack-Davis JK, Eblen ST, Zecevic M, Boerner SA, Tarcsafalvi A, Diaz HB, Marshall MS, Weber MJ, Parsons JT, Catling AD. PAK1 phosphorylation of MEK1 regulates fibronectin-stimulated MAPK activation. J Cell Biol. 2003 Jul 21;162(2):281-91. PMID:12876277 doi:10.1083/jcb.200212141
9. ↑ Zhou GL, Zhuo Y, King CC, Fryer BH, Bokoch GM, Field J. Akt phosphorylation of serine 21 on Pak1 modulates Nck binding and cell migration. Mol Cell Biol. 2003 Nov;23(22):8058-69. PMID:14585966
10. ↑ Zhou H, Kramer RH. Integrin engagement differentially modulates epithelial cell motility by RhoA/ROCK and PAK1. J Biol Chem. 2005 Mar 18;280(11):10624-35. Epub 2004 Dec 17. PMID:15611088 doi:10.1074/jbc.M411900200
11. ↑ Vadlamudi RK, Barnes CJ, Rayala S, Li F, Balasenthil S, Marcus S, Goodson HV, Sahin AA, Kumar R. p21-activated kinase 1 regulates microtubule dynamics by phosphorylating tubulin cofactor B. Mol Cell Biol. 2005 May;25(9):3726-36. PMID:15831477 doi:25/9/3726
12. ↑ Talukder AH, Meng Q, Kumar R. CRIPak, a novel endogenous Pak1 inhibitor. Oncogene. 2006 Mar 2;25(9):1311-9. PMID:16278681 doi:1209172
13. ↑ Rider L, Shatrova A, Feener EP, Webb L, Diakonova M. JAK2 tyrosine kinase phosphorylates PAK1 and regulates PAK1 activity and functions. J Biol Chem. 2007 Oct 19;282(42):30985-96. Epub 2007 Aug 28. PMID:17726028 doi:10.1074/jbc.M701794200
14. ↑ Mayhew MW, Jeffery ED, Sherman NE, Nelson K, Polefrone JM, Pratt SJ, Shabanowitz J, Parsons JT, Fox JW, Hunt DF, Horwitz AF. Identification of phosphorylation sites in betaPIX and PAK1. J Cell Sci. 2007 Nov 15;120(Pt 22):3911-8. PMID:17989089 doi:10.1242/jcs.008177
15. ↑ Nie J, Sun C, Faruque O, Ye G, Li J, Liang Q, Chang Z, Yang W, Han X, Shi Y. Synapses of amphids defective (SAD-A) kinase promotes glucose-stimulated insulin secretion through activation of p21-activated kinase (PAK1) in pancreatic beta-Cells. J Biol Chem. 2012 Jul 27;287(31):26435-44. doi: 10.1074/jbc.M112.378372. Epub, 2012 Jun 5. PMID:22669945 doi:10.1074/jbc.M112.378372