Cytoskeleton remodeling - Regulation of actin cytoskeleton by Rho GTPases

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:

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   Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science (New York, N.Y.) 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
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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
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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