RHO GTPases activate PAKs

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Homo sapiens
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The PAKs (p21-activated kinases) are a family of serine/threonine kinases mainly implicated in cytoskeletal rearrangements. All PAKs share a conserved catalytic domain located at the carboxyl terminus and a highly conserved motif in the amino terminus known as p21-binding domain (PBD) or Cdc42/Rac interactive binding (CRIB) domain. There are six mammalian PAKs that can be divided into two classes: class I (or conventional) PAKs (PAK1-3) and class II PAKs (PAK4-6). Conventional PAKs are important regulators of cytoskeletal dynamics and cell motility and are additionally implicated in transcription through MAPK (mitogen-activated protein kinase) cascades, death and survival signaling and cell cycle progression (Chan and Manser 2012).

PAK1, PAK2 and PAK3 are direct effectors of RAC1 and CDC42 GTPases. RAC1 and CDC42 bind to the CRIB domain. This binding induces a conformational change that disrupts inactive PAK homodimers and relieves autoinhibition of the catalytic carboxyl terminal domain (Manser et al. 1994, Manser et al. 1995, Zhang et al. 1998, Lei et al. 2000, Parrini et al. 2002; reviewed by Daniels and Bokoch 1999, Szczepanowska 2009). Autophosphorylation of a conserved threonine residue in the catalytic domain of PAKs (T423 in PAK1, T402 in PAK2 and T436 in PAK3) is necessary for the kinase activity of PAK1, PAK2 and PAK3. Autophosphorylation of PAK1 serine residue S144, PAK2 serine residue S141, and PAK3 serine residue S154 disrupts association of PAKs with RAC1 or CDC42 and enhances kinase activity (Lei et al. 2000, Chong et al. 2001, Parrini et al. 2002, Jung and Traugh 2005, Wang et al. 2011). LIMK1 is one of the downstream targets of PAK1 and is activated through PAK1-mediated phosphorylation of the threonine residue T508 within its activation loop (Edwards et al. 1999). Further targets are the myosin regulatory light chain (MRLC), myosin light chain kinase (MLCK), filamin, cortactin, p41Arc (a subunit of the Arp2/3 complex), caldesmon, paxillin and RhoGDI, to mention a few (Szczepanowska 2009).

Class II PAKs also have a CRIB domain, but lack a defined autoinhibitory domain and proline-rich regions. They do not require GTPases for their kinase activity, but their interaction with RAC or CDC42 affects their subcellular localization. Only conventional PAKs will be annotated here.

Literature References
PubMed ID Title Journal Year
10975528 Structure of PAK1 in an autoinhibited conformation reveals a multistage activation switch

Lei, M, Lu, W, Meng, W, Parrini, MC, Eck, MJ, Mayer, BJ, Harrison, SC

Cell 2000
7559638 Molecular cloning of a new member of the p21-Cdc42/Rac-activated kinase (PAK) family

Manser, E, Chong, C, Zhao, ZS, Leung, T, Michael, G, Hall, C, Lim, L

J. Biol. Chem. 1995
9535855 Interaction of Rac1 with GTPase-activating proteins and putative effectors. A comparison with Cdc42 and RhoA

Zhang, B, Chernoff, J, Zheng, Y

J. Biol. Chem. 1998
11278486 The mechanism of PAK activation. Autophosphorylation events in both regulatory and kinase domains control activity

Chong, C, Tan, L, Lim, L, Manser, E

J Biol Chem 2001
16204230 Regulation of the interaction of Pak2 with Cdc42 via autophosphorylation of serine 141

Jung, JH, Traugh, JA

J Biol Chem 2005
10470034 p21-activated protein kinase: a crucial component of morphological signaling?

Daniels, RH, Bokoch, GM

Trends Biochem Sci 1999
22340718 PAKs in human disease

Chan, PM, Manser, E

Prog Mol Biol Transl Sci 2012
21098037 Mechanistic studies of the autoactivation of PAK2: a two-step model of cis initiation followed by trans amplification

Wang, J, Wu, JW, Wang, ZX

J. Biol. Chem. 2011
8107774 A brain serine/threonine protein kinase activated by Cdc42 and Rac1

Manser, E, Leung, T, Salihuddin, H, Zhao, ZS, Lim, L

Nature 1994
11804587 Pak1 kinase homodimers are autoinhibited in trans and dissociated upon activation by Cdc42 and Rac1

Parrini, MC, Lei, M, Harrison, SC, Mayer, BJ

Mol Cell 2002
19513348 Involvement of Rac/Cdc42/PAK pathway in cytoskeletal rearrangements

Szczepanowska, J

Acta Biochim Pol 2009
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