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).<p>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.
View original pathway at:Reactome.</div>
Nakai K, Suzuki Y, Kihira H, Wada H, Fujioka M, Ito M, Nakano T, Kaibuchi K, Shiku H, Nishikawa M.; ''Regulation of myosin phosphatase through phosphorylation of the myosin-binding subunit in platelet activation.''; PubMedEurope PMCScholia
Dharmawardhane S, Brownson D, Lennartz M, Bokoch GM.; ''Localization of p21-activated kinase 1 (PAK1) to pseudopodia, membrane ruffles, and phagocytic cups in activated human neutrophils.''; PubMedEurope PMCScholia
Amano M, Ito M, Kimura K, Fukata Y, Chihara K, Nakano T, Matsuura Y, Kaibuchi K.; ''Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase).''; PubMedEurope PMCScholia
Jung JH, Traugh JA.; ''Regulation of the interaction of Pak2 with Cdc42 via autophosphorylation of serine 141.''; PubMedEurope PMCScholia
Wilkes MC, Repellin CE, Hong M, Bracamonte M, Penheiter SG, Borg JP, Leof EB.; ''Erbin and the NF2 tumor suppressor Merlin cooperatively regulate cell-type-specific activation of PAK2 by TGF-beta.''; PubMedEurope PMCScholia
Chu J, Pham NT, Olate N, Kislitsyna K, Day MC, LeTourneau PA, Kots A, Stewart RH, Laine GA, Cox CS, Uray K.; ''Biphasic regulation of myosin light chain phosphorylation by p21-activated kinase modulates intestinal smooth muscle contractility.''; PubMedEurope PMCScholia
Wang J, Wu JW, Wang ZX.; ''Mechanistic studies of the autoactivation of PAK2: a two-step model of cis initiation followed by trans amplification.''; PubMedEurope PMCScholia
Ikebe M, Hartshorne DJ, Elzinga M.; ''Identification, phosphorylation, and dephosphorylation of a second site for myosin light chain kinase on the 20,000-dalton light chain of smooth muscle myosin.''; PubMedEurope PMCScholia
Weed SA, Du Y, Parsons JT.; ''Translocation of cortactin to the cell periphery is mediated by the small GTPase Rac1.''; PubMedEurope PMCScholia
Edwards DC, Sanders LC, Bokoch GM, Gill GN.; ''Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics.''; PubMedEurope PMCScholia
Leung T, Chen XQ, Manser E, Lim L.; ''The p160 RhoA-binding kinase ROK alpha is a member of a kinase family and is involved in the reorganization of the cytoskeleton.''; PubMedEurope PMCScholia
Webb BA, Zhou S, Eves R, Shen L, Jia L, Mak AS.; ''Phosphorylation of cortactin by p21-activated kinase.''; PubMedEurope PMCScholia
Parrini MC, Lei M, Harrison SC, Mayer BJ.; ''Pak1 kinase homodimers are autoinhibited in trans and dissociated upon activation by Cdc42 and Rac1.''; PubMedEurope PMCScholia
Sumi T, Matsumoto K, Nakamura T.; ''Specific activation of LIM kinase 2 via phosphorylation of threonine 505 by ROCK, a Rho-dependent protein kinase.''; PubMedEurope PMCScholia
Ikebe M, Hartshorne DJ.; ''Phosphorylation of smooth muscle myosin at two distinct sites by myosin light chain kinase.''; PubMedEurope PMCScholia
Qi Q, Liu X, Brat DJ, Ye K.; ''Merlin sumoylation is required for its tumor suppressor activity.''; PubMedEurope PMCScholia
Grassart A, Meas-Yedid V, Dufour A, Olivo-Marin JC, Dautry-Varsat A, Sauvonnet N.; ''Pak1 phosphorylation enhances cortactin-N-WASP interaction in clathrin-caveolin-independent endocytosis.''; PubMedEurope PMCScholia
Ohashi K, Nagata K, Maekawa M, Ishizaki T, Narumiya S, Mizuno K.; ''Rho-associated kinase ROCK activates LIM-kinase 1 by phosphorylation at threonine 508 within the activation loop.''; PubMedEurope PMCScholia
Watanabe T, Hosoya H, Yonemura S.; ''Regulation of myosin II dynamics by phosphorylation and dephosphorylation of its light chain in epithelial cells.''; PubMedEurope PMCScholia
Yi C, Wilker EW, Yaffe MB, Stemmer-Rachamimov A, Kissil JL.; ''Validation of the p21-activated kinases as targets for inhibition in neurofibromatosis type 2.''; PubMedEurope PMCScholia
Hathaway DR, Adelstein RS.; ''Human platelet myosin light chain kinase requires the calcium-binding protein calmodulin for activity.''; PubMedEurope PMCScholia
Zeng Q, Lagunoff D, Masaracchia R, Goeckeler Z, Côté G, Wysolmerski R.; ''Endothelial cell retraction is induced by PAK2 monophosphorylation of myosin II.''; PubMedEurope PMCScholia
García-García E, Rosales C.; ''Signal transduction during Fc receptor-mediated phagocytosis.''; PubMedEurope PMCScholia
Pudas R, Kiema TR, Butler PJ, Stewart M, Ylänne J.; ''Structural basis for vertebrate filamin dimerization.''; PubMedEurope PMCScholia
Kissil JL, Wilker EW, Johnson KC, Eckman MS, Yaffe MB, Jacks T.; ''Merlin, the product of the Nf2 tumor suppressor gene, is an inhibitor of the p21-activated kinase, Pak1.''; PubMedEurope PMCScholia
Ishizaki T, Maekawa M, Fujisawa K, Okawa K, Iwamatsu A, Fujita A, Watanabe N, Saito Y, Kakizuka A, Morii N, Narumiya S.; ''The small GTP-binding protein Rho binds to and activates a 160 kDa Ser/Thr protein kinase homologous to myotonic dystrophy kinase.''; PubMedEurope PMCScholia
Iwasaki T, Murata-Hori M, Ishitobi S, Hosoya H.; ''Diphosphorylated MRLC is required for organization of stress fibers in interphase cells and the contractile ring in dividing cells.''; PubMedEurope PMCScholia
Szczepanowska J.; ''Involvement of Rac/Cdc42/PAK pathway in cytoskeletal rearrangements.''; PubMedEurope PMCScholia
Knaus UG, Wang Y, Reilly AM, Warnock D, Jackson JH.; ''Structural requirements for PAK activation by Rac GTPases.''; PubMedEurope PMCScholia
Kimura K, Ito M, Amano M, Chihara K, Fukata Y, Nakafuku M, Yamamori B, Feng J, Nakano T, Okawa K, Iwamatsu A, Kaibuchi K.; ''Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase)''; PubMedEurope PMCScholia
Sanders LC, Matsumura F, Bokoch GM, de Lanerolle P.; ''Inhibition of myosin light chain kinase by p21-activated kinase.''; PubMedEurope PMCScholia
Indik ZK, Park JG, Hunter S, Schreiber AD.; ''The molecular dissection of Fc gamma receptor mediated phagocytosis.''; PubMedEurope PMCScholia
Hirokawa Y, Tikoo A, Huynh J, Utermark T, Hanemann CO, Giovannini M, Xiao GH, Testa JR, Wood J, Maruta H.; ''A clue to the therapy of neurofibromatosis type 2: NF2/merlin is a PAK1 inhibitor.''; PubMedEurope PMCScholia
Aizawa H, Wakatsuki S, Ishii A, Moriyama K, Sasaki Y, Ohashi K, Sekine-Aizawa Y, Sehara-Fujisawa A, Mizuno K, Goshima Y, Yahara I.; ''Phosphorylation of cofilin by LIM-kinase is necessary for semaphorin 3A-induced growth cone collapse.''; PubMedEurope PMCScholia
Zhang B, Chernoff J, Zheng Y.; ''Interaction of Rac1 with GTPase-activating proteins and putative effectors. A comparison with Cdc42 and RhoA.''; PubMedEurope PMCScholia
Daniels RH, Bokoch GM.; ''p21-activated protein kinase: a crucial component of morphological signaling?''; PubMedEurope PMCScholia
Vidal C, Geny B, Melle J, Jandrot-Perrus M, Fontenay-Roupie M.; ''Cdc42/Rac1-dependent activation of the p21-activated kinase (PAK) regulates human platelet lamellipodia spreading: implication of the cortical-actin binding protein cortactin.''; PubMedEurope PMCScholia
Goeckeler ZM, Masaracchia RA, Zeng Q, Chew TL, Gallagher P, Wysolmerski RB.; ''Phosphorylation of myosin light chain kinase by p21-activated kinase PAK2.''; PubMedEurope PMCScholia
Katoh K, Kano Y, Amano M, Onishi H, Kaibuchi K, Fujiwara K.; ''Rho-kinase--mediated contraction of isolated stress fibers.''; PubMedEurope PMCScholia
Lei M, Lu W, Meng W, Parrini MC, Eck MJ, Mayer BJ, Harrison SC.; ''Structure of PAK1 in an autoinhibited conformation reveals a multistage activation switch.''; PubMedEurope PMCScholia
Vadlamudi RK, Li F, Adam L, Nguyen D, Ohta Y, Stossel TP, Kumar R.; ''Filamin is essential in actin cytoskeletal assembly mediated by p21-activated kinase 1.''; PubMedEurope PMCScholia
Chong C, Tan L, Lim L, Manser E.; ''The mechanism of PAK activation. Autophosphorylation events in both regulatory and kinase domains control activity.''; PubMedEurope PMCScholia
Rong R, Surace EI, Haipek CA, Gutmann DH, Ye K.; ''Serine 518 phosphorylation modulates merlin intramolecular association and binding to critical effectors important for NF2 growth suppression.''; PubMedEurope PMCScholia
Weihing RR.; ''Actin-binding and dimerization domains of HeLa cell filamin.''; PubMedEurope PMCScholia
Manser E, Leung T, Salihuddin H, Zhao ZS, Lim L.; ''A brain serine/threonine protein kinase activated by Cdc42 and Rac1.''; PubMedEurope PMCScholia
Manser E, Chong C, Zhao ZS, Leung T, Michael G, Hall C, Lim L.; ''Molecular cloning of a new member of the p21-Cdc42/Rac-activated kinase (PAK) family.''; PubMedEurope PMCScholia
Chen TY, Illing M, Molday LL, Hsu YT, Yau KW, Molday RS.; ''Subunit 2 (or beta) of retinal rod cGMP-gated cation channel is a component of the 240-kDa channel-associated protein and mediates Ca(2+)-calmodulin modulation.''; PubMedEurope PMCScholia
Nimmerjahn F, Ravetch JV.; ''Fcgamma receptors: old friends and new family members.''; PubMedEurope PMCScholia
Robinson JM, Badwey JA.; ''Rapid association of cytoskeletal remodeling proteins with the developing phagosomes of human neutrophils.''; PubMedEurope PMCScholia
Ruskamo S, Ylänne J.; ''Structure of the human filamin A actin-binding domain.''; PubMedEurope PMCScholia
Chew TL, Masaracchia RA, Goeckeler ZM, Wysolmerski RB.; ''Phosphorylation of non-muscle myosin II regulatory light chain by p21-activated kinase (gamma-PAK).''; PubMedEurope PMCScholia
Amano M, Nakayama M, Kaibuchi K.; ''Rho-kinase/ROCK: A key regulator of the cytoskeleton and cell polarity.''; PubMedEurope PMCScholia
Phagocytosis is one of the important innate immune responses that function to eliminate invading infectious agents. Monocytes, macrophages, and neutrophils are the professional phagocytic cells. Phagocytosis is a complex process involving the recognition of invading foreign particles by specific types of phagocytic receptors and the subsequent internalization of the particles. Fc gamma receptors (FCGRs) are among the best studied phagocytic receptors that bind to Fc portion of immunoglobulin G (IgG). Through their antigen binding F(ab) end, antibodies bind to specific antigen while their constant (Fc) region binds to FCGRs on phagocytes. The clustering of FCGRs by IgG antibodies on the phagocyte initiates a variety of signals, which lead, through the reorganisation of actin cytoskeleton and membrane remodelling, to the formation of pseudopod and phagosome. Fc gamma receptors are classified into three classes: FCGRI, FCGRII and FCGRIII. Each class of these FCGRs consists of several individual isoforms. Among all these isoforms FCGRI, FCGRIIA and FCGRIIIA, are able to mediate phagocytosis (Joshi et al. 2006, Garcia Garcia & Rosales 2002, Nimmerjahn & Ravetch 2006).
All known myosin phosphatases consist of PP1 beta and both a large and a small myosin phosphatase targetting (Mypt) subunit. The large Mypt targets PP1 beta to myosin and determines the substrate specifity of the phosphatase. The Large Mypt subunit is encoded by one of three human genes, PPP1R12A (MYPT1), PPP1R12B (MYPT2) and PPP1R12C. Only MYPT1 is represented here. The small subunit is an alternative transcript of MYPT2. The function of the small Mypt subunit remains unclear, but because it is known to interact directly with myosin and the large Mypt it is thought to have an unspecified regulatory role.
RHO associated, coiled-coil containing protein kinases ROCK1 and ROCK2 consist of a serine/threonine kinase domain, a coiled-coil region, a RHO-binding domain and a plekstrin homology (PH) domain interspersed with a cysteine-rich region. The PH domain inhibits the kinase activity of ROCKs by an intramolecular fold. ROCKs are activated by binding of the GTP-bound RHO GTPases RHOA, RHOB and RHOC to the RHO binding domain of ROCKs (Ishizaki et al. 1996, Leung et al. 1996), which disrupts the autoinhibitory fold. Once activated, ROCK1 and ROCK2 phosphorylate target proteins, many of which are involved in the stabilization of actin filaments and generation of actin-myosin contractile force. ROCKs phosphorylate LIM kinases LIMK1 and LIMK2, enabling LIMKs to phosphorylate cofilin, an actin depolymerizing factor, and thereby regulate the reorganization of the actin cytoskeleton (Ohashi et al. 2000, Sumi et al. 2001). ROCKs phosphorylate MRLC (myosin regulatory light chain), which stimulates the activity of non-muscle myosin II (NMM2), an actin-based motor protein involved in cell migration, polarity formation and cytokinesis (Amano et al. 1996, Riento and Ridley 2003, Watanabe et al. 2007, Amano et al. 2010). ROCKs also phosphorylate the myosin phosphatase targeting subunit (MYPT1) of MLC phosphatase, inhibiting the phosphatase activity and preventing dephosphorylation of MRLC. This pathway acts synergistically with phosphorylation of MRLC by ROCKs towards stimulation of non-muscle myosin II activity (Kimura et al. 1996, Amano et al. 2010).
Class 2 myosins are a set of protein complexes that bind actin and hydrolyse ATP, acting as molecular motors. They consist of two myosin heavy chains , two essential light chains and two regulatory light chains (MRLCs). Smooth muscle and non-muscle myosin isoforms are a subset of Class 2 myosin complexes. The nomenclature for isoforms is misleading, as non-muscle isoforms can be found in smooth muscle. The 4 smooth muscle isoforms all have heavy chains encoded by MYH11. The non-muscle isoforms have heavy chains encoded by MYH9, MYH10 or MYH14 (NMHC-IIA, B and C). The essential light chain (LC17) common to smooth and non-muscle isoforms is encoded by MYL6. The regulatory light chain (LC20) is encoded by either MYL9, giving a slightly more basic protein that is referred to as the smooth muscle LC20 isoform, and MRLC2, giving a more acidic isoform referred to as the non-muscle LC20 isoform.
Class 2 myosins play a crucial role in a variety of cellular processes, including cell migration, polarity formation, and cytokinesis.
Nonmuscle myosin II (NMM2) is an actin-based motor protein that plays a crucial role in a variety of cellular processes, including smooth muscle contraction, cell migration, polarity formation, and cytokinesis. NMM2 consists of two myosin heavy chains encoded by MYH9, MYH10, MYH14 (NMHC-IIA, B and C) or MYH11, two copies of MYL6 essential light chain protein, and two regulatory light chains (MRLCs), MYL9 and MYL12B. Myosin II activity is stimulated by phosphorylation of MRLC. Diphosphorylation at Thr-19 and Ser-20 (commonly referred in the literature as Thr-18 and Ser-19) increases both actin-activated Mg2+ ATPase activity and the stability of myosin II filaments; monophosphorylation at Ser-20 is less effective (Ikebe and Hartshorne 1985, Ikebe et al. 1988). Kinases responsible for the phosphorylation include myosin light chain kinase (MLCK), ROCK kinase, citron kinase, myotonic dystrophy kinase-related CDC42-binding protein kinase, and Zipper-interacting protein (ZIP) kinase. ROCK activity has been shown to regulate MRLC phosphorylation by directly mono- or diphosphorylating MRLC (Amano et al., 1996, Ueda et al., 2002, Watanabe et al. 2007).
Class 2 myosins are a set of protein complexes that bind actin and hydrolyse ATP, acting as molecular motors. They consist of two myosin heavy chains , two essential light chains and two regulatory light chains (MRLCs). Smooth muscle and non-muscle myosin isoforms are a subset of Class 2 myosin complexes. The nomenclature for isoforms is misleading, as non-muscle isoforms can be found in smooth muscle. The 4 smooth muscle isoforms all have heavy chains encoded by MYH11. The non-muscle isoforms have heavy chains encoded by MYH9, MYH10 or MYH14 (NMHC-IIA, B and C). The essential light chain (LC17) common to smooth and non-muscle isoforms is encoded by MYL6. The regulatory light chain (LC20) is encoded by either MYL9, giving a slightly more basic protein that is referred to as the smooth muscle LC20 isoform, and MRLC2, giving a more acidic isoform referred to as the non-muscle LC20 isoform.
Class 2 myosins play a crucial role in a variety of cellular processes, including cell migration, polarity formation, and cytokinesis.
All known myosin phosphatases consist of PP1 beta and both a large and a small myosin phosphatase targetting (Mypt) subunit. The large Mypt targets PP1 beta to myosin and determines the substrate specifity of the phosphatase. The Large Mypt subunit is encoded by one of three human genes, PPP1R12A (MYPT1), PPP1R12B (MYPT2) and PPP1R12C. Only MYPT1 is represented here. The small subunit is an alternative transcript of MYPT2. The function of the small Mypt subunit remains unclear, but because it is known to interact directly with myosin and the large Mypt it is thought to have an unspecified regulatory role.
PAK1, a downstream effector of CDC42 and RAC1, is found localized in phagosomes. Upon activation, PAK1 phosphorylates LIMK, which directly phosphorylates and inactivates cofilin, a protein that mediates depolymerization of actin filaments. Thus, RAC and CDC42 coordinate actin dynamics by inducing actin polymerization via ARP2/3 on one hand, and inhibiting actin depolyerization via LIMK and cofilin on the other (Garcia-Garcia & Rosales 2002). PAK1 exists as homodimer in a trans-inhibited conformation. The kinase inhibitory (KI) domain of one PAK1 molecule binds to the C-terminal catalytic domain of the other and inhibits catalytic activity. GTPases RAC1/CDC42 bind the GBD domain of PAK1 thereby altering the conformation of the KI domain, relieving inhibition of its catalytic domain, and allowing PAK1 autophosphorylation that is required for full kinase activity (Parrini et al. 2002, Zhao & Manser 2005).
LIM kinases are serine protein kinases with a unique combination of two N-terminal LIM motifs, a central PDZ domain, and a C-terminal protein kinase domain. LIMK1 is one of the downstream targets of PAK1 and is activated through phosphorylation by PAK1 on T508 within its activation loop (Edwards et al. 1999, Aizawa et al. 2001). LIM-kinase is responsible for the tight regulation of the activity of cofilin (a protein that depolymerizes actin filaments) and thus maintains the balance between actin assembly and disassembly. Phosphorylated cofilin is inactive, resulting in stabilization of the actin cytoskeleton.
In non-muscle cells, phosphorylation of myosin II regulates actomyosin contractility. The level of myosin phosphorylation depends mainly on the balance of two enzymes, the Ca2+-dependent MLC kinase (MLCK), and myosin phosphatase (MLCP). Phosphorylation of the regulatory light chain of myosin II (MRLC) induces its interaction with actin, activating myosin ATPase and resulting in enhanced cell contractility. Myosin phosphatase decreases MRLC phosphorylation, which inhibits binding to filamentous actin and stress fibre formation (Kimura et al. 1996, Nakai et al. 1997, Katoh et al. 2001, Iwasaki et al. 2001).
PAKs can associate with cortactin (CTTN), a cortical actin binding protein, irrespective of the activation status of PAKs. Once activated, PAKs phosphorylate cortactin, predominantly at Ser113 in the first actin-binding repeat. Cortactin phosphorylation modulates its interaction with actin and actin cytoskeleton regulators and is involved in cell motility (Weed et al. 1998, Vidal et al. 2002, Webb et al. 2006, Grassart et al. 2010, Moshfegh et al. 2014).
Once calcium influx occurs, calmodulin is activated by the binding of calcium. The active calmodulin complex binds and activates the smooth muscle myosin light chain kinase (Hathaway and Adelstein 1979, Webb 2003).
Binding of PAK1, PAK2 or PAK3 to GTP-bound RAC1 or CDC42 disrupts PAK homodimers and allows PAK autophosphorylation. 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 GTPases and enhances kinase activity (Lei et al. 2000, Chong et al. 2001, Parrini et al. 2002, Jung and Traugh 2005, Wang et al. 2011).
PAK2, activated by CDC42 or RAC1 RHO GTPases, phosphorylates myosin regulatory light chain (MRLC, MYL9 or MYL12B) of the non-muscle myosin II complex on threonine residue T19 (also labeled in literature as T18). This leads to the rearrangement of the actin cytoskeleton and cell retraction (Chew et al. 1998, Zeng et al. 2000).
PAK1 phosphorylates the regulatory subunit MYPT1 (PPP1R12A) of the myosin phosphatase complex on threonine residue T696, thereby inhibiting the catalytic activity of the myosin phosphatase and indirectly increasing phosphorylation of the myosin regulatory light chain (MRLC) (Chu et al. 2013).
MYLK (MLCK) is a Ca2+/calmodulin-dependent myosin light chain kinase that phosphorylates myosin regulatory light chains (MRLC) MYL9 and MYL12B at threonine T19 and serine S20 (also labeled in literature as T18 and S19) (Ikebe and Hartshorne 1985, Ikebe et al. 1986).
PAK1 and PAK2 phosphorylate and inactivate MYLK (MLCK), a myosin light chain kinase. It is assumed that PAK1 phosphorylates the same sites as PAK2. MYLK serine residues phosphorylated by PAK2 were determined using rabbit recombinant MYLK and human PAK2. Rabbit MYLK serines S439 and S991 are conserved in human MYLK and match S1208 and S1759 (Sanders et al. 1999, Goeckeler et al. 2000). Please note that the recombinant rabbit MYLK sequence is shorter than the canonical human MYLK sequence and corresponds to human MYLK transcription isoforms that lack the first 922 amino acids present in the canonical MYLK isoform.
NF2 (Merlin) is a product of the tumor suppressor gene neurofibromatosis type 2 (NF2). NF2 binds to the PBD of PAK1 and prevents its activation (Kissil et al. 2003). In primary schwannoma tumor samples derived from patients with germline mutations in the NF2 gene, PAK1 activity is highly elevated (Yi et al. 2008) and essential for the malignant growth of NF2-deficient cells (Hirokawa et al. 2004). In complex with ERBIN (ERBB2IP), NF2 may also be involved in the inhibition of PAK2 activation (Wilkes et al. 2009).
The localization and function of NF2 may be modulated by PAK2-mediated phosphorylation and subsequent sumoylation (Rong et al. 2004, Qi et al. 2014).
The CRIB domain of PAK1 binds to the C-terminal part (repeat 23) of filamin A (FLNA). The interaction is enhanced upon PAK1 activation (Vadlamudi et al. 2002).
Activated PAK1 phosphorylates FLNA (filamin A) on serine residue S2152 in vitro and in vivo. FLNA is involved in PAK1-induced formation of membrane ruffles (Vadlamudi et al. 2002).
Inactive p21-associated kinases (PAKs), PAK1, PAK2 and PAK3, form homodimers that are autoinhibited through in trans interaction between the inhibitory N-terminus of one PAK molecule and the catalytic domain of the other PAK molecule. PAK3, like other PAK isoforms, is a direct effector of RAC1 and CDC42 GTPases. RAC1 and CDC42 bind to a highly conserved motif in the amino terminus of PAK3 known as p21-binding domain (PBD) or Cdc42/Rac interactive binding (CRIB) domain. This binding induces a conformational change that disrupts PAK3 homodimers and relieves autoinhibition of the catalytic carboxyl terminal domain, thereby inducing autophosphorylation at several sites and enabling the phosphorylation of exogenous substrates (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).
Inactive p21-associated kinases (PAKs), PAK1, PAK2 and PAK3, form homodimers that are autoinhibited through in trans interaction between the inhibitory N-terminus of one PAK molecule and the catalytic domain of the other PAK molecule. PAK2, like other PAK isoforms, is a direct effector of RAC1 and CDC42 GTPases. RAC1 and CDC42 bind to a highly conserved motif in the amino terminus of PAK2 known as p21-binding domain (PBD) or Cdc42/Rac interactive binding (CRIB) domain. This binding induces a conformational change that disrupts PAK2 homodimers and relieves autoinhibition of the catalytic carboxyl terminal domain, thereby inducing autophosphorylation at several sites and enabling the phosphorylation of exogenous substrates (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).
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(FCGR) dependent
phagocytosismuscle/non-muscle
myosin IImuscle/non-muscle
myosin IIAnnotated Interactions
PAK1 exists as homodimer in a trans-inhibited conformation. The kinase inhibitory (KI) domain of one PAK1 molecule binds to the C-terminal catalytic domain of the other and inhibits catalytic activity. GTPases RAC1/CDC42 bind the GBD domain of PAK1 thereby altering the conformation of the KI domain, relieving inhibition of its catalytic domain, and allowing PAK1 autophosphorylation that is required for full kinase activity (Parrini et al. 2002, Zhao & Manser 2005).
The localization and function of NF2 may be modulated by PAK2-mediated phosphorylation and subsequent sumoylation (Rong et al. 2004, Qi et al. 2014).
muscle/non-muscle
myosin IImuscle/non-muscle
myosin IImuscle/non-muscle
myosin IImuscle/non-muscle
myosin II