Kinase Subfamily ROCK
Kinase Classification: Group AGC: Family DMPK: Subfamily ROCK
ROCK subfamily kinases modulate the cytoskeleton in response to Rho GTPase signaling.
Evolution
ROCK is an animal specific kinase duplicated in vertebrates (ROCK1, ROCK2), and with homologs in Drosophila (rok) and C. elegans (let-502).
Domain Structure
ROCK kinases are long multidomain proteins of ~1300 AA. They have an N-terminal kinase domain with the AGC-specific kinase domain tail, followed by a central coiled-coil region, HR1 domain, Rho-binding, HR and PH domains. The PH domain is split by an inserted CRD (cysteine-rich Zn finger motif).
Functions
Rock is activated by the small GTPase Rho and modulates the cytoskeleton by phosphorylation of a wide array of cytoskeletal proteins. Binding of Rho-GTP to the RBD relieves an intramolecular inhibition and activates the kinase activity. This activity in conserved in Drosophila, C. elegans, and vertebrates.
Substrates include LIMK kinase which phosphorylates and inhibits cofilin, blocking its actin-depolymerizing function [1], and myosin regulatory light chain (MRLC2/MYL12B in human, sqh in Drosophila) that regulates Myosin II. MRLC is also activated by the DRAK kinase [2].
Human ROCK1 is known to phosphorylate the insulin signaling protein IRS-1, and mouse knockouts and biochemical analysis show that it is required for insulin signaling [3].
Drosophila rok is well-studied in the planar cell polarity pathway, where it is genetically downstream of frizzled and dishevelled and phosphorylates the non-muscle myosin light chain, regulating Myosin II [4]. It is activated by Rho1, the single homolog of human RhoA/B/C which also activate human ROCK.
References
- Ohashi K, Nagata K, Maekawa M, Ishizaki T, Narumiya S, and Mizuno K. Rho-associated kinase ROCK activates LIM-kinase 1 by phosphorylation at threonine 508 within the activation loop. J Biol Chem. 2000 Feb 4;275(5):3577-82. DOI:10.1074/jbc.275.5.3577 |
- Neubueser D and Hipfner DR. Overlapping roles of Drosophila Drak and Rok kinases in epithelial tissue morphogenesis. Mol Biol Cell. 2010 Aug 15;21(16):2869-79. DOI:10.1091/mbc.E10-04-0328 |
- Lee DH, Shi J, Jeoung NH, Kim MS, Zabolotny JM, Lee SW, White MF, Wei L, and Kim YB. Targeted disruption of ROCK1 causes insulin resistance in vivo. J Biol Chem. 2009 May 1;284(18):11776-80. DOI:10.1074/jbc.C900014200 |
- Winter CG, Wang B, Ballew A, Royou A, Karess R, Axelrod JD, and Luo L. Drosophila Rho-associated kinase (Drok) links Frizzled-mediated planar cell polarity signaling to the actin cytoskeleton. Cell. 2001 Apr 6;105(1):81-91. DOI:10.1016/s0092-8674(01)00298-7 |
