Abstract
Ras and Rho proteins are GTP-regulated molecular switches that control multiple signaling pathways in eukaryotic cells. Ras was among the first identified oncogenes, and it appears mutated in many forms of human cancer. It mainly promotes proliferation and survival through the MAPK pathway and the PI3K/AKT pathways, respectively. However, the myriad proteins close to the plasma membrane that activate or inhibit Ras make it a major regulator of many apparently unrelated pathways. On the other hand, Rho is weakly oncogenic by itself, but it critically regulates microfilament dynamics; that is, actin polymerization, disassembly and contraction. Polymerization is driven mainly by the Arp2/3 complex and formins, whereas contraction depends on myosin mini-filament assembly and activity. These two pathways intersect at numerous points: from Ras-dependent triggering of Rho activators, some of which act through PI3K, to mechanical feedback driven by actomyosin action. Here, we describe the main points of connection between the Ras and Rho pathways as they coordinately drive oncogenic transformation. We emphasize the biochemical crosstalk that drives actomyosin contraction driven by Ras in a Rho-dependent manner. We also describe possible routes of mechanical feedback through which myosin II activation may control Ras/Rho activation.
Highlights
Small GTPases are molecular switches that cycle between active GTP-bound and inactive GDP-bound forms and regulate a variety of cellular signaling events, including growth, cellular differentiation, cell motility and survival
The mechanism, which depends on RIAM and kindlin [241], drives the ligation of talin to the tail of the beta chain of several integrin receptors, connecting the integrin to actin as part of a mechanosensitive molecular clutch that connects adhesion size and dynamics with adhesive force, actin polymerization and organization and cell migration [242]
Numerous targets can interact with Ras and Rho GTPases and extensive crosstalk and cooperation exist
Summary
Small GTPases are molecular switches that cycle between active GTP-bound and inactive GDP-bound forms and regulate a variety of cellular signaling events, including growth, cellular differentiation, cell motility and survival. RhoA is best known for its ability to promote the formation of actin stress fibers and focal adhesions, whereas Cdc and Rac regulate the formation of filopodia and lamellipodia, respectively They all are heavily involved in cell migration through the control of actin dynamics [14,15,16]; in addition, they modulate gene expression, cell cycle progression, and cell survival [17,18]. Using Caco-2 cells as a model, Makrodouli et al demonstrated that mutations in H-, K-Ras or B-Raf induced different changes in cell morphology due to regulation of different Rho GTPases [49] They demonstrated that mutations in BrafV600E promoted a significant increase in cell migration and invasion through activation of RhoA GTPase in a MERK–ERK-dependent fashion. We will focus on the connections between Ras and Rho signaling as they converge on the protein myosin II, a major generator of mechanical force in normal and cancer cells
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