Ral GTPases: corrupting the exocyst in cancer cells

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The Ras-like small G-proteins RalA and RalB have achieved some notoriety as components of one of a growing variety of candidate Ras effector pathways. Recent work has demonstrated that Ral GTPase activation is required to support both the initiation and maintenance of tumorigenic transformation of human cells. The mechanistic basis for this support remains to be defined. However, the discovery that the exocyst is a direct effector complex for activated Ral proteins suggests that mobilization of polarized exocytosis might be a basic component of the biological framework supporting tumorigenic progression.

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Initiation and maintenance of tumorigenic transformation

Exploration of Ras function in the budding and fission yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe generated the first insights that these proteins represent hubs in signal-transduction networks, coupling regulatory cues to the functional activation of multiple downstream effector pathways required to drive an appropriate physiological response [10]. This concept has translated to mammalian cells, where it appears that at least three major effector pathways mediate Ras

Regulation of the exocyst

Control of specialized secretory events through the Sec6/8 complex, or exocyst, has been defined as a fundamental aspect of Ral GTPase-dependent cell regulation 23, 24, 25. The exocyst is a multisubunit complex that is conserved among eukaryotes and comprises of the core elements Sec3, Sec5, Sec6, Sec8, Sec10, Sec15, Exo70 and Exo84. Characterization of exocyst assembly and function in yeasts suggests that the exocyst is a dynamic complex assembled from subunits that form a targeting patch on

Exocytosis and cancer

Ostensibly, propagation of growth-regulatory signals and control of the exocyst appear to be rather disparate occupations for Ral GTPases. However, compelling observations from studies of the behavior of normal and cancerous human epithelial cells in organotypic culture models suggest that prominent linkages between these processes support both cell proliferation and survival 39, 40. As described above, the exocyst is required to maintain the molecular polarity of epithelial cell membranes

Concluding remarks

The recent elucidation and manipulation of the Ral GTPase regulatory network in cultured cells has indicted that these proteins act as key offenders in the corruption of the core cell-autonomous machinery driving oncogenic transformation. RalA and RalB are, respectively, required to support anchorage-independent proliferation and suppress apoptosis in human cancer cells. Chronic Ral activation is sufficient in some contexts to induce oncogenic transformation and is a chief mediator of the

Acknowledgements

M.A.W. is supported by the National Institutes of Health (CA71443) and the Robert E. Welch Foundation (I-1414).

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