Spatiotemporal regulation of the Pak1 kinase.

Pak1 (p21-activated kinase 1) is a key regulator of the actin cytoskeleton, adhesion and cell motility. Such biological roles require a tight spatial and kinetic control of its localization and activity. We summarize here the current knowledge on Pak1 dynamics in vivo. Inactive dimeric Pak1 is mainly cytosolic. Localized interaction with the activators Cdc42-GTP and Rac1-GTP stimulates the kinase at the sites of cellular protrusions. Moreover, Pak1 is dynamically engaged into multiprotein complexes forming adhesions to the extracellular matrix. Cutting edge microscopy technologies on living cells are finally shedding light on the intricate spatiotemporal mechanisms regulating Pak1.

[1]  Borivoj Vojnovic,et al.  Spatially Distinct Binding of Cdc42 to PAK1 and N-WASP in Breast Carcinoma Cells , 2005, Molecular and Cellular Biology.

[2]  E. Manser,et al.  PAK and other Rho-associated kinases--effectors with surprisingly diverse mechanisms of regulation. , 2005, The Biochemical journal.

[3]  J. Chernoff,et al.  The genetics of Pak , 2004, Journal of Cell Science.

[4]  C. J. Barnes,et al.  p41‐Arc subunit of human Arp2/3 complex is a p21‐activated kinase‐1‐interacting substrate , 2004, EMBO reports.

[5]  G. Borisy,et al.  Cell Migration: Integrating Signals from Front to Back , 2003, Science.

[6]  Jonathan Chernoff,et al.  Pak1 and PIX regulate contact inhibition during epithelial wound healing , 2003, The EMBO journal.

[7]  Wei Lu,et al.  Directional Sensing Requires Gβγ-Mediated PAK1 and PIXα-Dependent Activation of Cdc42 , 2003, Cell.

[8]  T. Stossel,et al.  Filamin is essential in actin cytoskeletal assembly mediated by p21-activated kinase 1 , 2002, Nature Cell Biology.

[9]  C. Turner,et al.  Paxillin-dependent paxillin kinase linker and p21-activated kinase localization to focal adhesions involves a multistep activation pathway. , 2002, Molecular biology of the cell.

[10]  D. Webb,et al.  GIT1 functions in a motile, multi-molecular signaling complex that regulates protrusive activity and cell migration. , 2002, Journal of cell science.

[11]  K. Hahn,et al.  Integrins regulate GTP-Rac localized effector interactions through dissociation of Rho-GDI , 2002, Nature Cell Biology.

[12]  J. Lippincott-Schwartz,et al.  Studying protein dynamics in living cells , 2001, Nature Reviews Molecular Cell Biology.

[13]  J. Chernoff,et al.  Temporal and Spatial Distribution of Activated Pak1 in Fibroblasts , 2000, The Journal of cell biology.

[14]  Wange Lu,et al.  Structure of PAK1 in an Autoinhibited Conformation Reveals a Multistage Activation Switch , 2000, Cell.

[15]  D. C. Edwards,et al.  Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics , 1999, Nature Cell Biology.

[16]  Maria Carla Parrini,et al.  Pak1 kinase homodimers are autoinhibited in trans and dissociated upon activation by Cdc42 and Rac1. , 2002, Molecular cell.

[17]  X. Q. Chen,et al.  PAK kinases are directly coupled to the PIX family of nucleotide exchange factors. , 1998, Molecular cell.