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Strochlic TI
,
Viaud J
,
Rennefahrt UE
,
Anastassiadis T
,
Peterson JR
.
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Phospholipid-enriched membranes such as the plasma membrane can serve as direct regulators of kinase signaling. Pak1 is involved in growth factor signaling at the plasma membrane, and its dysregulation is implicated in cancer. Pak1 adopts an autoinhibited conformation that is relieved upon binding to membrane-bound Rho GTPases Rac1 or Cdc42, but whether lipids also regulate Pak1 in vivo is unknown. We show here that phosphoinositides, particularly PIP(2), potentiate Rho-GTPase-mediated Pak1 activity. A positively charged region of Pak1 binds to phosphoinositide-containing membranes, and this interaction is essential for membrane recruitment and activation of Pak1 in response to extracellular signals. Our results highlight an active role for lipids as allosteric regulators of Pak1 and suggest that Pak1 is a "coincidence detector" whose activation depends on GTPases present in phosphoinositide-rich membranes. These findings expand the role of phosphoinositides in kinase signaling and suggest how altered phosphoinositide metabolism may upregulate Pak1 activity in cancer cells.
Arias-Romero,
A tale of two Paks.
2008,
Pubmed
Beeser,
Role of group A p21-activated kinases in activation of extracellular-regulated kinase by growth factors.
2005,
Pubmed
Bokoch,
Biology of the p21-activated kinases.
2003,
Pubmed
Bokoch,
A GTPase-independent mechanism of p21-activated kinase activation. Regulation by sphingosine and other biologically active lipids.
1998,
Pubmed
Deacon,
An isoform-selective, small-molecule inhibitor targets the autoregulatory mechanism of p21-activated kinase.
2008,
Pubmed
Dharmawardhane,
Localization of p21-activated kinase 1 (PAK1) to pinocytic vesicles and cortical actin structures in stimulated cells.
1997,
Pubmed
Ding,
The renaturable 69- and 63-kDa protein kinases that undergo rapid activation in chemoattractant-stimulated guinea pig neutrophils are p21-activated kinases.
1996,
Pubmed
Di Paolo,
Phosphoinositides in cell regulation and membrane dynamics.
2006,
Pubmed
Doughman,
Membrane ruffling requires coordination between type Ialpha phosphatidylinositol phosphate kinase and Rac signaling.
2003,
Pubmed
Gao,
Rational design and characterization of a Rac GTPase-specific small molecule inhibitor.
2004,
Pubmed
Heo,
PI(3,4,5)P3 and PI(4,5)P2 lipids target proteins with polybasic clusters to the plasma membrane.
2006,
Pubmed
Hoffman,
Structure of the Rho family GTP-binding protein Cdc42 in complex with the multifunctional regulator RhoGDI.
2000,
Pubmed
Knaus,
Structural requirements for PAK activation by Rac GTPases.
1998,
Pubmed
Manser,
Expression of constitutively active alpha-PAK reveals effects of the kinase on actin and focal complexes.
1997,
Pubmed
Molli,
PAK signaling in oncogenesis.
2009,
Pubmed
Newton,
Lipid activation of protein kinases.
2009,
Pubmed
Papayannopoulos,
A polybasic motif allows N-WASP to act as a sensor of PIP(2) density.
2005,
Pubmed
Pelish,
Secramine inhibits Cdc42-dependent functions in cells and Cdc42 activation in vitro.
2006,
Pubmed
Peterson,
Chemical inhibition of N-WASP by stabilization of a native autoinhibited conformation.
2004,
Pubmed
,
Xenbase
Peterson,
A chemical inhibitor of N-WASP reveals a new mechanism for targeting protein interactions.
2001,
Pubmed
,
Xenbase
Pitcher,
G protein-coupled receptor kinases.
1998,
Pubmed
Rennefahrt,
Specificity profiling of Pak kinases allows identification of novel phosphorylation sites.
2007,
Pubmed
Sells,
Characterization of Pak2p, a pleckstrin homology domain-containing, p21-activated protein kinase from fission yeast.
1998,
Pubmed
Sells,
Epitope-tag vectors for eukaryotic protein production.
1995,
Pubmed
Takahashi,
Identification of novel membrane-binding domains in multiple yeast Cdc42 effectors.
2007,
Pubmed
van den Bout,
PIP5K-driven PtdIns(4,5)P2 synthesis: regulation and cellular functions.
2009,
Pubmed
Viaud,
An allosteric kinase inhibitor binds the p21-activated kinase autoregulatory domain covalently.
2009,
Pubmed
Wild,
The p21-activated protein kinase-related kinase Cla4 is a coincidence detector of signaling by Cdc42 and phosphatidylinositol 4-phosphate.
2004,
Pubmed
Zhou,
Opposing roles for Akt1 and Akt2 in Rac/Pak signaling and cell migration.
2006,
Pubmed
