Rho cell motility signaling pathway
RhoA is a small G-protein in the Rho family that regulates cell morphology via actin cytoskeleton reorganization in response to extracellular signals. The majority of RhoA activations is due to disruption of intramolecular autoinhibitory interactions. Changes in cytoskeletal structure and other aspects of cell structure are involved in cell morphology. RhoA is activated by GEF factors, and repressed by GAPs. GEFs are guanine nucleotide exchange factors. GAPs are GTPase-activating proteins. The RhoGAP ARHGAP1 also acts as a GAP for Rac and CDC42. Active RhoA increases the stability of actin-based structures such as stress fibers and focal adhesions. Several different factors downstream of RhoA act on cytoskeletal structures to affect stability of these structures. Rock1 provides a direct link from RhoA to cell morphology through phosphorylation of the myosin light chain. Rock1 also phosphorylates and activates LIM kinase, which phosphorylates cofilin. Cofilin stimulates actin depolymerization and changes in cell structure, and phosphorylation of cofilin by LIM kinase represses this activity. According to Nimnual et al. Rho activity is reduced as a result of Rac-induced redox-dependent inhibition. Related Disease: Non-syndromic deafness appears to be the result of amino acid substitutions in the 52-amino acid C-terminal end of Dia 1. This modification creates a constituatively active Dia 1 protein. A mutation in the RhoGAP Oligophrenin-1 is thought to contribute to a form of mental retardation due to loss of Rho inhibition in neuronal development.
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REFERENCES: Liqun Luo, RHO GTPases in neuronal morphogenesis. Nature, 2000, vol 1 Dec, 173-179. Nimnual AS, Taylor LJ, Bar-Sagi D., Redox-dependent downregulation of Rho by Rac. Nat Cell Biol 2003 Mar;5(3):236-41 Ridley, A.J., Rho GTPases and cell migration. J Cell Sci. 2001 Aug;114(Pt 15):2713-22
