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Type II p21-activated kinases (PAKs) are regulated by an autoinhibitory pseudosubstrate.

Ha BH, Davis MJ, Chen C, Lou HJ, Gao J, Zhang R, Krauthammer M, Halaban R, Schlessinger J, Turk BE, Boggon TJ
Proc Natl Acad Sci U S A 109 16107-12 (2012)
Related entries: 4fie, 4fif, 4fig, 4fih, 4fij

Cited: 53 times
EuropePMC logo PMID: 22988085

Abstract

The type II p21-activated kinases (PAKs) are key effectors of RHO-family GTPases involved in cell motility, survival, and proliferation. Using a structure-guided approach, we discovered that type II PAKs are regulated by an N-terminal autoinhibitory pseudosubstrate motif centered on a critical proline residue, and that this regulation occurs independently of activation loop phosphorylation. We determined six X-ray crystal structures of either full-length PAK4 or its catalytic domain, that demonstrate the molecular basis for pseudosubstrate binding to the active state with phosphorylated activation loop. We show that full-length PAK4 is constitutively autoinhibited, but mutation of the pseudosubstrate releases this inhibition and causes increased phosphorylation of the apoptotic regulation protein Bcl-2/Bcl-X(L) antagonist causing cell death and cellular morphological changes. We also find that PAK6 is regulated by the pseudosubstrate region, indicating a common type II PAK autoregulatory mechanism. Finally, we find Src SH3, but not β-PIX SH3, can activate PAK4. We provide a unique understanding for type II PAK regulation.

Reviews - 4fii mentioned but not cited (1)

  1. Rho family GTPase signaling through type II p21-activated kinases. Chetty AK, Ha BH, Boggon TJ. Cell Mol Life Sci 79 598 (2022)

Articles - 4fii mentioned but not cited (6)

  1. 6-Hydroxydopamine induces secretion of PARK7/DJ-1 via autophagy-based unconventional secretory pathway. Urano Y, Mori C, Fuji A, Konno K, Yamamoto T, Yashirogi S, Ando M, Saito Y, Noguchi N. Autophagy 14 1943-1958 (2018)
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  4. PAK4 crystal structures suggest unusual kinase conformational movements. Zhang EY, Ha BH, Boggon TJ. Biochim Biophys Acta Proteins Proteom 1866 356-365 (2018)
  5. A Phosphoinositide-Binding Protein Acts in the Trafficking Pathway of Hemoglobin in the Malaria Parasite Plasmodium falciparum. Mukherjee A, Crochetière MÈ, Sergerie A, Amiar S, Thompson LA, Ebrahimzadeh Z, Gagnon D, Lauruol F, Bourgeois A, Galaup T, Roucheray S, Hallée S, Padmanabhan PK, Stahelin RV, Dacks JB, Richard D. mBio 13 e0323921 (2022)
  6. Molecular basis for integrin adhesion receptor binding to p21-activated kinase 4 (PAK4). Ha BH, Yigit S, Natarajan N, Morse EM, Calderwood DA, Boggon TJ. Commun Biol 5 1257 (2022)


Reviews citing this publication (20)

  1. PAK signalling during the development and progression of cancer. Radu M, Semenova G, Kosoff R, Chernoff J. Nat Rev Cancer 14 13-25 (2014)
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  6. Regulation of Janus kinases by SOCS proteins. Kershaw NJ, Murphy JM, Lucet IS, Nicola NA, Babon JJ. Biochem Soc Trans 41 1042-1047 (2013)
  7. Signaling, Regulation, and Specificity of the Type II p21-activated Kinases. Ha BH, Morse EM, Turk BE, Boggon TJ. J Biol Chem 290 12975-12983 (2015)
  8. Disordered Protein Kinase Regions in Regulation of Kinase Domain Cores. Gógl G, Kornev AP, Reményi A, Taylor SS. Trends Biochem Sci 44 300-311 (2019)
  9. Group II p21-activated kinases as therapeutic targets in gastrointestinal cancer. Shao YG, Ning K, Li F. World J Gastroenterol 22 1224-1235 (2016)
  10. The p21-activated kinases in neural cytoskeletal remodeling and related neurological disorders. Zhang K, Wang Y, Fan T, Zeng C, Sun ZS. Protein Cell 13 6-25 (2022)
  11. p21-activated kinases and gastrointestinal cancer. He H, Baldwin GS. Biochim Biophys Acta 1833 33-39 (2013)
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  17. The significance of PAK4 in signaling and clinicopathology: A review. Yu X, Huang C, Liu J, Shi X, Li X. Open Life Sci 17 586-598 (2022)
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  20. P-21 Activated Kinases in Liver Disorders. Qiu X, Xu H, Wang K, Gao F, Xu X, He H. Cancers (Basel) 15 551 (2023)

Articles citing this publication (26)

  1. Identification of a major determinant for serine-threonine kinase phosphoacceptor specificity. Chen C, Ha BH, Thévenin AF, Lou HJ, Zhang R, Yip KY, Peterson JR, Gerstein M, Kim PM, Filippakopoulos P, Knapp S, Boggon TJ, Turk BE. Mol Cell 53 140-147 (2014)
  2. PAK4 promotes kinase-independent stabilization of RhoU to modulate cell adhesion. Dart AE, Box GM, Court W, Gale ME, Brown JP, Pinder SE, Eccles SA, Wells CM. J Cell Biol 211 863-879 (2015)
  3. Activated-PAK4 predicts worse prognosis in breast cancer and promotes tumorigenesis through activation of PI3K/AKT signaling. He LF, Xu HW, Chen M, Xian ZR, Wen XF, Chen MN, Du CW, Huang WH, Wu JD, Zhang GJ. Oncotarget 8 17573-17585 (2017)
  4. PAK4 Methylation by SETD6 Promotes the Activation of the Wnt/β-Catenin Pathway. Vershinin Z, Feldman M, Chen A, Levy D. J Biol Chem 291 6786-6795 (2016)
  5. An in cellulo-derived structure of PAK4 in complex with its inhibitor Inka1. Baskaran Y, Ang KC, Anekal PV, Chan WL, Grimes JM, Manser E, Robinson RC. Nat Commun 6 8681 (2015)
  6. Leucine-rich repeat kinase 2 interacts with p21-activated kinase 6 to control neurite complexity in mammalian brain. Civiero L, Cirnaru MD, Beilina A, Rodella U, Russo I, Belluzzi E, Lobbestael E, Reyniers L, Hondhamuni G, Lewis PA, Van den Haute C, Baekelandt V, Bandopadhyay R, Bubacco L, Piccoli G, Cookson MR, Taymans JM, Greggio E. J Neurochem 135 1242-1256 (2015)
  7. Structural Basis for Noncanonical Substrate Recognition of Cofilin/ADF Proteins by LIM Kinases. Hamill S, Lou HJ, Turk BE, Boggon TJ. Mol Cell 62 397-408 (2016)
  8. PAK6 Phosphorylates 14-3-3γ to Regulate Steady State Phosphorylation of LRRK2. Civiero L, Cogo S, Kiekens A, Morganti C, Tessari I, Lobbestael E, Baekelandt V, Taymans JM, Chartier-Harlin MC, Franchin C, Arrigoni G, Lewis PA, Piccoli G, Bubacco L, Cookson MR, Pinton P, Greggio E. Front Mol Neurosci 10 417 (2017)
  9. Comprehensive profiling of the STE20 kinase family defines features essential for selective substrate targeting and signaling output. Miller CJ, Lou HJ, Simpson C, van de Kooij B, Ha BH, Fisher OS, Pirman NL, Boggon TJ, Rinehart J, Yaffe MB, Linding R, Turk BE. PLoS Biol 17 e2006540 (2019)
  10. PAK4 interacts with p85 alpha: implications for pancreatic cancer cell migration. King H, Thillai K, Whale A, Arumugam P, Eldaly H, Kocher HM, Wells CM. Sci Rep 7 42575 (2017)
  11. The Cdc42 Effector Kinase PAK4 Localizes to Cell-Cell Junctions and Contributes to Establishing Cell Polarity. Selamat W, Tay PL, Baskaran Y, Manser E. PLoS One 10 e0129634 (2015)
  12. CDC42 binds PAK4 via an extended GTPase-effector interface. Ha BH, Boggon TJ. Proc Natl Acad Sci U S A 115 531-536 (2018)
  13. Discovery and the structural basis of a novel p21-activated kinase 4 inhibitor. Ryu BJ, Kim S, Min B, Kim KY, Lee JS, Park WJ, Lee H, Kim SH, Park S. Cancer Lett 349 45-50 (2014)
  14. NMR binding and crystal structure reveal that intrinsically-unstructured regulatory domain auto-inhibits PAK4 by a mechanism different from that of PAK1. Wang W, Lim L, Baskaran Y, Manser E, Song J. Biochem Biophys Res Commun 438 169-174 (2013)
  15. Functional cross-talk between Cdc42 and two downstream targets, Par6B and PAK4. Jin D, Durgan J, Hall A. Biochem J 467 293-302 (2015)
  16. PAK6 targets to cell-cell adhesions through its N-terminus in a Cdc42-dependent manner to drive epithelial colony escape. Morse EM, Sun X, Olberding JR, Ha BH, Boggon TJ, Calderwood DA. J Cell Sci 129 380-393 (2016)
  17. PAK4 Kinase Activity Plays a Crucial Role in the Podosome Ring of Myeloid Cells. Foxall E, Staszowska A, Hirvonen LM, Georgouli M, Ciccioli M, Rimmer A, Williams L, Calle Y, Sanz-Moreno V, Cox S, Jones GE, Wells CM. Cell Rep 29 3385-3393.e6 (2019)
  18. INKA2, a novel p53 target that interacts with the serine/threonine kinase PAK4. Liu YY, Tanikawa C, Ueda K, Matsuda K. Int J Oncol 54 1907-1920 (2019)
  19. P21-activated kinase 4 in pancreatic acinar cells is activated by numerous gastrointestinal hormones/neurotransmitters and growth factors by novel signaling, and its activation stimulates secretory/growth cascades. Ramos-Alvarez I, Jensen RT. Am J Physiol Gastrointest Liver Physiol 315 G302-G317 (2018)
  20. Solution structures and biophysical analysis of full-length group A PAKs reveal they are monomeric and auto-inhibited in cis. Sorrell FJ, Kilian LM, Elkins JM. Biochem J 476 1037-1051 (2019)
  21. A novel phosphorylation site at Ser130 adjacent to the pseudosubstrate domain contributes to the activation of protein kinase C-δ. Gong J, Holewinski RJ, Van Eyk JE, Steinberg SF. Biochem J 473 311-320 (2016)
  22. Recognition of physiological phosphorylation sites by p21-activated kinase 4. Chetty AK, Sexton JA, Ha BH, Turk BE, Boggon TJ. J Struct Biol 211 107553 (2020)
  23. Proximity proteomics identifies PAK4 as a component of Afadin-Nectin junctions. Baskaran Y, Tay FP, Ng EYW, Swa CLF, Wee S, Gunaratne J, Manser E. Nat Commun 12 5315 (2021)
  24. The subcellular localization of type I p21-activated kinases is controlled by the disordered variable region and polybasic sequences. Sun X, Su VL, Calderwood DA. J Biol Chem 294 14319-14332 (2019)
  25. Mbt/PAK4 together with SRC modulates N-Cadherin adherens junctions in the developing Drosophila eye. Pütz SM. Biol Open 8 bio038406 (2019)
  26. Melanoma-associated mutants within the serine-rich domain of PAK5 direct kinase activity to mitogenic pathways. LaPak KM, Vroom DC, Garg AA, Guan X, Hays JL, Song JW, Burd CE. Oncotarget 9 25386-25401 (2018)


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