Pathway Map Details

Cytoskeleton remodeling_Regulation of actin cytoskeleton by Rho GTPases



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Object list (links open in MetaCore):

RhoA, Arp2/3, Myosin II, MLCK, Rac1, Fascin, MLCP (reg), MLCP (cat), MyHC, MRLC, MELC, WASF1(WAVE1), PAK1, LIMK1, ROCK, WASP, Filamin A, Actin cytoskeletal, Cofilin, CDC42, Actin, LIMK2, Profilin

Description:

Regulation of actin cytoskeleton by Rho GTPases

Ras homolog gene family, member A ( RhoA ) downstream effector Rho-associated, coiled-coil containing protein kinase ( ROCK ) directly phosphorylates LIM domain kinases 1 and 2 ( LIMK1 and LIMK2 ) that in turn phosphorylates Cofilin. Cofilin exhibits Actin -depolymerizing activity followed by reorganization of the Actin cytoskeleton [1].

The activated ROCK also subsequently phosphorylates and inactivates the Myosin light chain phosphatase ( MLCP ) [2] that attenuates Myosin light chains ( MELC ) (myosin light chains) and Myosin light chain regulatory ( MRLC ) phosphorylation [3].

Ras-related C3 botulinum toxin substrate 1 ( Rac1 ) downstream effector P21 protein-activated kinase 1 ( PAK1 ) directly phosphorylates LIMK1 [4], inhibits MLCK [5], activates MRLC [6] and ARP2 actin-related protein 2 and 3 ( Arp2/3 ) complex [7]. Arp2/3 complex nucleates new Actin filaments from the sides of preexisting filaments. [8]. Also, WAS protein family member 1 ( WAVE ) plays a critical role downstream of Rac in that it regulates the Actin cytoskeleton required for membrane ruffling. WAVE share function as an inducer of Actin reorganization through profiling [9].

Cell division cycle 42 ( CDC42 ) initiates Wiskott-Aldrich syndrome ( WASP )/ Arp2/3 nucleation of Actin [10]. Recruitment of factors, including Profilin, by WASP stimulates cellular Actin -based motility [11].

References:

  1. Maekawa M, Ishizaki T, Boku S, Watanabe N, Fujita A, Iwamatsu A, Obinata T, Ohashi K, Mizuno K, Narumiya S
    Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science 1999 Aug 6;285(5429):895-8
  2. Riento K, Ridley AJ
    Rocks: multifunctional kinases in cell behaviour. Nature reviews. Molecular cell biology. 2003 Jun;4(6):446-56
  3. Pfitzer G
    Invited review: regulation of myosin phosphorylation in smooth muscle. Journal of applied physiology (Bethesda, Md. : 1985) 2001 Jul;91(1):497-503
  4. Edwards DC, Sanders LC, Bokoch GM, Gill GN
    Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics. Nature cell biology 1999 Sep;1(5):253-9
  5. Sanders LC, Matsumura F, Bokoch GM, de Lanerolle P
    Inhibition of myosin light chain kinase by p21-activated kinase. Science 1999 Mar 26;283(5410):2083-5
  6. Sells MA, Boyd JT, Chernoff J
    p21-activated kinase 1 (Pak1) regulates cell motility in mammalian fibroblasts. The Journal of cell biology 1999 May 17;145(4):837-49
  7. Vadlamudi RK, Li F, Barnes CJ, Bagheri-Yarmand R, Kumar R
    p41-Arc subunit of human Arp2/3 complex is a p21-activated kinase-1-interacting substrate. EMBO reports 2004 Feb;5(2):154-60
  8. Dayel MJ, Mullins RD
    Activation of Arp2/3 complex: addition of the first subunit of the new filament by a WASP protein triggers rapid ATP hydrolysis on Arp2. PLoS biology 2004 Apr;2(4):E91
  9. Miki H, Suetsugu S, Takenawa T
    WAVE, a novel WASP-family protein involved in actin reorganization induced by Rac. The EMBO journal 1998 Dec 1;17(23):6932-41
  10. Pollard TD, Blanchoin L, Mullins RD
    Molecular mechanisms controlling actin filament dynamics in nonmuscle cells. Annual review of biophysics and biomolecular structure 2000;29:545-76
  11. Yarar D, D'Alessio JA, Jeng RL, Welch MD
    Motility determinants in WASP family proteins. Molecular biology of the cell 2002 Nov;13(11):4045-59