Rho signaling, ROCK and mDia1, in transformation, metastasis and invasion

Abstract

The Rho subgroup of the Rho GTPases consisting of RhoA, RhoB and RhoC induces a specific type of actin cytoskeleton and carry out a variety of functions in the cell. mDia and ROCK are downstream effectors of Rho mediating Rho action on the actin cytoskeleton; mDia produces actin filaments by nucleation and polymerization and ROCK activate myosin to cross-link them for induction of actomyosin bundles and contractility. mDia is potentially linked to Rac activation and membrane ruffle formation through c-Srcinduced phosphorylation of focal adhesion proteins, and ROCK antagonizes this mDia action. Thus, cell morphogenesis, adhesion, and motility can be determined by the balance between mDia and ROCK activities. Though they are not oncogenes by themselves, overexpression of RhoA and RhoC are often found in clinical cancers, and RhoC has been repeatedly identified as a gene associated with metastasis. The Rho-ROCK pathway is implicated in Ras-mediated transformation, the amoeboid movement of tumor cells in the threedimensional matrix, and transmigration of tumor cells through the mesothelial monolayer. On the other hand, the Rho-mDia1 pathway is implicated in Src-mediated remodeling of focal adhesions and migration of tumor cells. There is also an indication that the Rho pathway other than ROCK is involved in Src-mediated induction of podosome and regulation of matrix metalloproteases. Thus, Rho mediates various phenotypes of malignant transformation by Ras and Src through its effectors, ROCK and mDia.

The guanine nucleotide exchange factor Arhgef5 plays crucial roles in Src-induced podosome formation

“…Thus, it seems that strict regulation of Cdc42 and Rac1, by their upstream regulators, is crucial for podosome organization. It has been shown that Src activates Rac1 through the Cas-Crk-DOCK180 complex and RhoA-Dia1 signaling (Narumiya et al, 2009). Taken together, these findings suggest that an appropriate interplay between these Rho family GTPases is involved in podosome formation and that the Src-Arhgef5-RhoA axis has a triggering role in the pathway leading to podosome formation.…”

Control of cell mechanics by RhoA and calcium fluxes during epithelial scattering

“…Mammalian diaphanous (mDia) is a formin protein that is activated upon Rho binding, resulting in nucleation of new actin filaments and polymerization that generates unbranched filaments, which is important in the formation of stress fiber contractile units. [23][24][25] Active RhoA recruits profilin, which binds G-actin to facilitate F-actin barbed end polymerization. 26 Phosphorylation of cofilin by LIM kinase results in a loss of cofilin activity and stabilization of actin filaments, which is the end result of RhoA-mediated activation of ROCK and, subsequently, of LIM kinase, the socalled RhoA-ROCK-LIM kinase-cofilin pathway.…”

The metastatic cancer cell cortex: An adaptation to enhance robust cell division in novel environments?

“…Firstly, it activates myosin II contraction, through its effector Rho Kinase, which provides the forces required to retract the spread margins of the cell, pulling the bulk of the cell upwards to from a sphere [16]. Secondly, based on its function in other contexts, RhoA likely helps to drive actin filament formation through the activation of a formin, mDia1 [24]. As a result, mitotic cells lacking Ect2, which have severely decreased RhoA activity, are much flatter, with a soft, disorganized actin cortex and associated spindle defects [16].…”