RHO GTPases activate PAKs (Homo sapiens)

From WikiPathways

Revision as of 10:49, 18 November 2015 by ReactomeTeam (Talk | contribs)
Jump to: navigation, search
9, 11, 17, 18, 23...2, 8, 22, 3310, 4246, 4819, 514, 479, 17, 25, 29, 36...12, 16, 27, 30, 31, 391, 6, 13, 15, 4011, 18, 36, 41, 492643, 452828cytosolp-T508-LIMK1p-S144,T423-PAK1 p-S141,T402-PAK2 MYH10 MYH10 GTP p-T696-PPP1R12A-Myosin phosphatasep-T19-MYL12B ATPCTTNRAC1 MYH14 ADPPPP1R12B MYH14 p-S2152-FLNA Ca2+ CALM1 FLNA ATPPPP1R12A p-S144,T423-PAK1PAK1,2,3:CDC42:GTP,RAC1:GTPMyosin phosphataseFLNAp-T19,S20-MYL9 PAK1 p-S154,T436-PAK3 MYH14 MYL6 CDC42 PAK1,2,3 dimerMYL12B MYH11 ATPCDC42:GTP, RAC1:GTPMYL9 ADPMYLK(1-1914)MYH10 ADPATPADPp-T696-PPP1R12A ATPMYH11 GTP p-S141,T402-PAK2PAK1 NF2 RAC1 ADPPPP1CB PAK2 p-S1208,S1759-MYLK(1-1914)p-T19-MRLC-Smoothmuscle/non-musclemyosin IIATPp-T19,S20-MYL12B PPP1CB ATPp-S144,T423-PAK1:FLNAPPP1R12B ATPADPMYL6 PAK1 p-S,T-PAK1,2,3p-T19-MYL9 PAK1 dimerp-S2152-FLNAPAK1:NF2p-S144,T423-PAK1 MYL6 LIMK1MYLK(1-1914) H2Op-S141,T402-PAK2 MYH11 p-S,T-PAK1,2PAK1 PAK2 PAK1,2,3ADPPiRHO GTPases ActivateROCKsPAK3 Fcgamma receptor(FCGR) dependentphagocytosisFLNA p-T19,S20-MRLC-smooth muscle/non-muscle myosin IIPAK3 MYH9 4xCa2+:CaMPAK2 Smoothmuscle/non-musclemyosin IICa2+ CALM1 p-S113-CTTNPAK1 PAK3 ADPp-S144,T423-PAK1 MYH9 MYH9 CDC42 MYLK:Ca2+:CALM1NF27, 20, 22, 24, 32...21, 34, 44, 5231533, 5, 14


Description

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>

Try the New WikiPathways

View approved pathways at the new wikipathways.org.

Quality Tags

Ontology Terms

 

Bibliography

View all...
  1. 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.''; PubMed Europe PMC Scholia
  2. 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.''; PubMed Europe PMC Scholia
  3. Moshfegh Y, Bravo-Cordero JJ, Miskolci V, Condeelis J, Hodgson L.; ''A Trio-Rac1-Pak1 signalling axis drives invadopodia disassembly.''; PubMed Europe PMC Scholia
  4. 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).''; PubMed Europe PMC Scholia
  5. Chan PM, Manser E.; ''PAKs in human disease.''; PubMed Europe PMC Scholia
  6. Jung JH, Traugh JA.; ''Regulation of the interaction of Pak2 with Cdc42 via autophosphorylation of serine 141.''; PubMed Europe PMC Scholia
  7. 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.''; PubMed Europe PMC Scholia
  8. Joshi T, Butchar JP, Tridandapani S.; ''Fcgamma receptor signaling in phagocytes.''; PubMed Europe PMC Scholia
  9. 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.''; PubMed Europe PMC Scholia
  10. Wang J, Wu JW, Wang ZX.; ''Mechanistic studies of the autoactivation of PAK2: a two-step model of cis initiation followed by trans amplification.''; PubMed Europe PMC Scholia
  11. 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.''; PubMed Europe PMC Scholia
  12. Weed SA, Du Y, Parsons JT.; ''Translocation of cortactin to the cell periphery is mediated by the small GTPase Rac1.''; PubMed Europe PMC Scholia
  13. Edwards DC, Sanders LC, Bokoch GM, Gill GN.; ''Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics.''; PubMed Europe PMC Scholia
  14. 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.''; PubMed Europe PMC Scholia
  15. Webb BA, Zhou S, Eves R, Shen L, Jia L, Mak AS.; ''Phosphorylation of cortactin by p21-activated kinase.''; PubMed Europe PMC Scholia
  16. Parrini MC, Lei M, Harrison SC, Mayer BJ.; ''Pak1 kinase homodimers are autoinhibited in trans and dissociated upon activation by Cdc42 and Rac1.''; PubMed Europe PMC Scholia
  17. Sumi T, Matsumoto K, Nakamura T.; ''Specific activation of LIM kinase 2 via phosphorylation of threonine 505 by ROCK, a Rho-dependent protein kinase.''; PubMed Europe PMC Scholia
  18. Webb RC.; ''Smooth muscle contraction and relaxation.''; PubMed Europe PMC Scholia
  19. Ikebe M, Hartshorne DJ.; ''Phosphorylation of smooth muscle myosin at two distinct sites by myosin light chain kinase.''; PubMed Europe PMC Scholia
  20. Qi Q, Liu X, Brat DJ, Ye K.; ''Merlin sumoylation is required for its tumor suppressor activity.''; PubMed Europe PMC Scholia
  21. 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.''; PubMed Europe PMC Scholia
  22. 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.''; PubMed Europe PMC Scholia
  23. Watanabe T, Hosoya H, Yonemura S.; ''Regulation of myosin II dynamics by phosphorylation and dephosphorylation of its light chain in epithelial cells.''; PubMed Europe PMC Scholia
  24. 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.''; PubMed Europe PMC Scholia
  25. Hathaway DR, Adelstein RS.; ''Human platelet myosin light chain kinase requires the calcium-binding protein calmodulin for activity.''; PubMed Europe PMC Scholia
  26. Zeng Q, Lagunoff D, Masaracchia R, Goeckeler Z, Côté G, Wysolmerski R.; ''Endothelial cell retraction is induced by PAK2 monophosphorylation of myosin II.''; PubMed Europe PMC Scholia
  27. García-García E, Rosales C.; ''Signal transduction during Fc receptor-mediated phagocytosis.''; PubMed Europe PMC Scholia
  28. Pudas R, Kiema TR, Butler PJ, Stewart M, Ylänne J.; ''Structural basis for vertebrate filamin dimerization.''; PubMed Europe PMC Scholia
  29. 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.''; PubMed Europe PMC Scholia
  30. 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.''; PubMed Europe PMC Scholia
  31. 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.''; PubMed Europe PMC Scholia
  32. Szczepanowska J.; ''Involvement of Rac/Cdc42/PAK pathway in cytoskeletal rearrangements.''; PubMed Europe PMC Scholia
  33. Knaus UG, Wang Y, Reilly AM, Warnock D, Jackson JH.; ''Structural requirements for PAK activation by Rac GTPases.''; PubMed Europe PMC Scholia
  34. 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)''; PubMed Europe PMC Scholia
  35. Sanders LC, Matsumura F, Bokoch GM, de Lanerolle P.; ''Inhibition of myosin light chain kinase by p21-activated kinase.''; PubMed Europe PMC Scholia
  36. Indik ZK, Park JG, Hunter S, Schreiber AD.; ''The molecular dissection of Fc gamma receptor mediated phagocytosis.''; PubMed Europe PMC Scholia
  37. 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.''; PubMed Europe PMC Scholia
  38. 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.''; PubMed Europe PMC Scholia
  39. Zhang B, Chernoff J, Zheng Y.; ''Interaction of Rac1 with GTPase-activating proteins and putative effectors. A comparison with Cdc42 and RhoA.''; PubMed Europe PMC Scholia
  40. Daniels RH, Bokoch GM.; ''p21-activated protein kinase: a crucial component of morphological signaling?''; PubMed Europe PMC Scholia
  41. 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.''; PubMed Europe PMC Scholia
  42. Goeckeler ZM, Masaracchia RA, Zeng Q, Chew TL, Gallagher P, Wysolmerski RB.; ''Phosphorylation of myosin light chain kinase by p21-activated kinase PAK2.''; PubMed Europe PMC Scholia
  43. Katoh K, Kano Y, Amano M, Onishi H, Kaibuchi K, Fujiwara K.; ''Rho-kinase--mediated contraction of isolated stress fibers.''; PubMed Europe PMC Scholia
  44. 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.''; PubMed Europe PMC Scholia
  45. 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.''; PubMed Europe PMC Scholia
  46. Chong C, Tan L, Lim L, Manser E.; ''The mechanism of PAK activation. Autophosphorylation events in both regulatory and kinase domains control activity.''; PubMed Europe PMC Scholia
  47. 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.''; PubMed Europe PMC Scholia
  48. Weihing RR.; ''Actin-binding and dimerization domains of HeLa cell filamin.''; PubMed Europe PMC Scholia
  49. Manser E, Leung T, Salihuddin H, Zhao ZS, Lim L.; ''A brain serine/threonine protein kinase activated by Cdc42 and Rac1.''; PubMed Europe PMC Scholia
  50. 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.''; PubMed Europe PMC Scholia
  51. 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.''; PubMed Europe PMC Scholia
  52. Nimmerjahn F, Ravetch JV.; ''Fcgamma receptors: old friends and new family members.''; PubMed Europe PMC Scholia
  53. Robinson JM, Badwey JA.; ''Rapid association of cytoskeletal remodeling proteins with the developing phagosomes of human neutrophils.''; PubMed Europe PMC Scholia
  54. Ruskamo S, Ylänne J.; ''Structure of the human filamin A actin-binding domain.''; PubMed Europe PMC Scholia
  55. Chew TL, Masaracchia RA, Goeckeler ZM, Wysolmerski RB.; ''Phosphorylation of non-muscle myosin II regulatory light chain by p21-activated kinase (gamma-PAK).''; PubMed Europe PMC Scholia
  56. Amano M, Nakayama M, Kaibuchi K.; ''Rho-kinase/ROCK: A key regulator of the cytoskeleton and cell polarity.''; PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
114777view16:27, 25 January 2021ReactomeTeamReactome version 75
113222view11:29, 2 November 2020ReactomeTeamReactome version 74
112445view15:39, 9 October 2020ReactomeTeamReactome version 73
101351view11:23, 1 November 2018ReactomeTeamreactome version 66
100889view20:57, 31 October 2018ReactomeTeamreactome version 65
100430view19:32, 31 October 2018ReactomeTeamreactome version 64
99979view16:15, 31 October 2018ReactomeTeamreactome version 63
99533view14:51, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99170view12:42, 31 October 2018ReactomeTeamreactome version 62
94017view13:51, 16 August 2017ReactomeTeamreactome version 61
93735view13:24, 16 August 2017ReactomeTeamreactome version 61
93636view11:29, 9 August 2017ReactomeTeamreactome version 61
89086view08:03, 22 August 2016EgonwOntology Term : 'signaling pathway' added !
86750view09:25, 11 July 2016ReactomeTeamreactome version 56
83333view10:49, 18 November 2015ReactomeTeamVersion54
81487view13:01, 21 August 2015ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
4xCa2+:CaMComplexR-HSA-74294 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
CALM1 ProteinP62158 (Uniprot-TrEMBL)
CDC42 ProteinP60953 (Uniprot-TrEMBL)
CDC42:GTP, RAC1:GTPComplexR-HSA-389778 (Reactome)
CTTNProteinQ14247 (Uniprot-TrEMBL)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
FLNA ProteinP21333 (Uniprot-TrEMBL)
FLNAComplexR-HSA-5669252 (Reactome)
Fcgamma receptor

(FCGR) dependent

phagocytosis		PathwayR-HSA-2029480 (Reactome) 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).
GTP MetaboliteCHEBI:15996 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
LIMK1ProteinP53667 (Uniprot-TrEMBL)
MYH10 ProteinP35580 (Uniprot-TrEMBL)
MYH11 ProteinP35749 (Uniprot-TrEMBL)
MYH14 ProteinQ7Z406 (Uniprot-TrEMBL)
MYH9 ProteinP35579 (Uniprot-TrEMBL)
MYL12B ProteinO14950 (Uniprot-TrEMBL)
MYL6 ProteinP60660 (Uniprot-TrEMBL)
MYL9 ProteinP24844 (Uniprot-TrEMBL)
MYLK(1-1914) ProteinQ15746 (Uniprot-TrEMBL)
MYLK(1-1914)ProteinQ15746 (Uniprot-TrEMBL)
MYLK:Ca2+:CALM1ComplexR-HSA-445764 (Reactome)
Myosin phosphataseComplexR-HSA-419080 (Reactome) 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.
NF2 ProteinP35240 (Uniprot-TrEMBL)
NF2ProteinP35240 (Uniprot-TrEMBL)
PAK1 ProteinQ13153 (Uniprot-TrEMBL)
PAK1 dimerComplexR-HSA-445002 (Reactome)
PAK1,2,3 dimerComplexR-HSA-399856 (Reactome)
PAK1,2,3:CDC42:GTP, RAC1:GTPComplexR-HSA-389782 (Reactome)
PAK1,2,3ComplexR-HSA-390765 (Reactome)
PAK1:NF2ComplexR-HSA-5669157 (Reactome)
PAK2 ProteinQ13177 (Uniprot-TrEMBL)
PAK3 ProteinO75914 (Uniprot-TrEMBL)
PPP1CB ProteinP62140 (Uniprot-TrEMBL)
PPP1R12A ProteinO14974 (Uniprot-TrEMBL)
PPP1R12B ProteinO60237 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
RAC1 ProteinP63000 (Uniprot-TrEMBL)
RHO GTPases Activate ROCKsPathwayR-HSA-5627117 (Reactome) 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).
Smooth

muscle/non-muscle

myosin II		ComplexR-HSA-419194 (Reactome) 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.
p-S,T-PAK1,2,3ComplexR-HSA-399836 (Reactome)
p-S,T-PAK1,2ComplexR-HSA-5668976 (Reactome)
p-S113-CTTNProteinQ14247 (Uniprot-TrEMBL)
p-S1208,S1759-MYLK(1-1914)ProteinQ15746 (Uniprot-TrEMBL)
p-S141,T402-PAK2 ProteinQ13177 (Uniprot-TrEMBL)
p-S141,T402-PAK2ProteinQ13177 (Uniprot-TrEMBL)
p-S144,T423-PAK1 ProteinQ13153 (Uniprot-TrEMBL)
p-S144,T423-PAK1:FLNAComplexR-HSA-5669239 (Reactome)
p-S144,T423-PAK1ProteinQ13153 (Uniprot-TrEMBL)
p-S154,T436-PAK3 ProteinO75914 (Uniprot-TrEMBL)
p-S2152-FLNA ProteinP21333 (Uniprot-TrEMBL)
p-S2152-FLNAComplexR-HSA-5669251 (Reactome)
p-T19,S20-MRLC-smooth muscle/non-muscle myosin IIComplexR-HSA-419195 (Reactome) 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).
p-T19,S20-MYL12B ProteinO14950 (Uniprot-TrEMBL)
p-T19,S20-MYL9 ProteinP24844 (Uniprot-TrEMBL)
p-T19-MRLC-Smooth

muscle/non-muscle

myosin II		ComplexR-HSA-5668934 (Reactome) 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.
p-T19-MYL12B ProteinO14950 (Uniprot-TrEMBL)
p-T19-MYL9 ProteinP24844 (Uniprot-TrEMBL)
p-T508-LIMK1ProteinP53667 (Uniprot-TrEMBL)
p-T696-PPP1R12A ProteinO14974 (Uniprot-TrEMBL)
p-T696-PPP1R12A-Myosin phosphataseComplexR-HSA-5668948 (Reactome) 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.

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
4xCa2+:CaMR-HSA-445797 (Reactome)
ADPArrowR-HSA-2029460 (Reactome)
ADPArrowR-HSA-442832 (Reactome)
ADPArrowR-HSA-5627775 (Reactome)
ADPArrowR-HSA-5668932 (Reactome)
ADPArrowR-HSA-5668947 (Reactome)
ADPArrowR-HSA-5668978 (Reactome)
ADPArrowR-HSA-5668984 (Reactome)
ADPArrowR-HSA-5669250 (Reactome)
ATPR-HSA-2029460 (Reactome)
ATPR-HSA-442832 (Reactome)
ATPR-HSA-5627775 (Reactome)
ATPR-HSA-5668932 (Reactome)
ATPR-HSA-5668947 (Reactome)
ATPR-HSA-5668978 (Reactome)
ATPR-HSA-5668984 (Reactome)
ATPR-HSA-5669250 (Reactome)
CDC42:GTP, RAC1:GTPArrowR-HSA-5627775 (Reactome)
CDC42:GTP, RAC1:GTPR-HSA-389788 (Reactome)
CTTNR-HSA-442832 (Reactome)
FLNAR-HSA-5669240 (Reactome)
H2OR-HSA-419232 (Reactome)
LIMK1R-HSA-2029460 (Reactome)
MYLK(1-1914)R-HSA-445797 (Reactome)
MYLK(1-1914)R-HSA-5668984 (Reactome)
MYLK:Ca2+:CALM1ArrowR-HSA-445797 (Reactome)
MYLK:Ca2+:CALM1mim-catalysisR-HSA-5668978 (Reactome)
Myosin phosphataseR-HSA-5668947 (Reactome)
Myosin phosphatasemim-catalysisR-HSA-419232 (Reactome)
NF2R-HSA-5669158 (Reactome)
PAK1 dimerR-HSA-5669158 (Reactome)
PAK1,2,3 dimerR-HSA-389788 (Reactome)
PAK1,2,3:CDC42:GTP, RAC1:GTPArrowR-HSA-389788 (Reactome)
PAK1,2,3:CDC42:GTP, RAC1:GTPR-HSA-5627775 (Reactome)
PAK1,2,3:CDC42:GTP, RAC1:GTPmim-catalysisR-HSA-5627775 (Reactome)
PAK1,2,3ArrowR-HSA-389788 (Reactome)
PAK1:NF2ArrowR-HSA-5669158 (Reactome)
PiArrowR-HSA-419232 (Reactome)
R-HSA-2029460 (Reactome) 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.
R-HSA-389788 (Reactome) 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. All PAK isoforms are direct effectors of RAC1 and CDC42 GTPases. RAC1 and CDC42 bind to a highly conserved motif in the amino terminus of PAK known as p21-binding domain (PBD) or Cdc42/Rac interactive binding (CRIB) domain. This binding induces a conformational change that disrupts PAK 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).
R-HSA-419232 (Reactome) 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).
R-HSA-442832 (Reactome) 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).
R-HSA-445797 (Reactome) 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).
R-HSA-5627775 (Reactome) 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).
R-HSA-5668932 (Reactome) 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).
R-HSA-5668947 (Reactome) 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).
R-HSA-5668978 (Reactome) 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).
R-HSA-5668984 (Reactome) 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.
R-HSA-5669158 (Reactome) 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).

R-HSA-5669240 (Reactome) 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).
R-HSA-5669250 (Reactome) 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).
Smooth

muscle/non-muscle

myosin II		ArrowR-HSA-419232 (Reactome)
Smooth

muscle/non-muscle

myosin II		R-HSA-5668932 (Reactome)
Smooth

muscle/non-muscle

myosin II		R-HSA-5668978 (Reactome)
p-S,T-PAK1,2,3ArrowR-HSA-5627775 (Reactome)
p-S,T-PAK1,2,3mim-catalysisR-HSA-442832 (Reactome)
p-S,T-PAK1,2mim-catalysisR-HSA-5668984 (Reactome)
p-S113-CTTNArrowR-HSA-442832 (Reactome)
p-S1208,S1759-MYLK(1-1914)ArrowR-HSA-5668984 (Reactome)
p-S141,T402-PAK2mim-catalysisR-HSA-5668932 (Reactome)
p-S144,T423-PAK1:FLNAArrowR-HSA-5669240 (Reactome)
p-S144,T423-PAK1:FLNAR-HSA-5669250 (Reactome)
p-S144,T423-PAK1:FLNAmim-catalysisR-HSA-5669250 (Reactome)
p-S144,T423-PAK1ArrowR-HSA-5669250 (Reactome)
p-S144,T423-PAK1R-HSA-5669240 (Reactome)
p-S144,T423-PAK1mim-catalysisR-HSA-2029460 (Reactome)
p-S144,T423-PAK1mim-catalysisR-HSA-5668947 (Reactome)
p-S2152-FLNAArrowR-HSA-5669250 (Reactome)
p-T19,S20-MRLC-smooth muscle/non-muscle myosin IIArrowR-HSA-5668978 (Reactome)
p-T19,S20-MRLC-smooth muscle/non-muscle myosin IIR-HSA-419232 (Reactome)
p-T19-MRLC-Smooth

muscle/non-muscle

myosin II		ArrowR-HSA-5668932 (Reactome)
p-T508-LIMK1ArrowR-HSA-2029460 (Reactome)
p-T696-PPP1R12A-Myosin phosphataseArrowR-HSA-5668947 (Reactome)

Retrieved from "https://classic.wikipathways.org/index.php/Pathway:WP3351"
Personal tools