Shc and the control of small GTPase dynamics in cellular anchorage

Specialized metazoan cells have diverse functions which require them to interact differently with the body's matrix scaffolds. Resident tissue cells, for instance, have strong anchorage capabilities and requirements that maintain tissue organization and structure, whereas blood cells need to release into a liquid environment for extended periods to function properly. Such differences in matrix adhesion are reflected in prominent shape differences, which in turn are controlled by small GTPases of the Rho and Ras families. These molecular switches coordinate cell fate signals with cytoskeletal dynamics, and are thus of major importance in understanding anchorage biology. The SHC1 gene expresses proteins that counterregulate Rho and Ras signals in response to adhesion status, and its isoforms are epigenetically regulated to bias GTPase signaling profiles towards epithelial-like or blood cell-like lineages. In this chapter, we review the Shc proteins as a specific example of how GTPases coordinate cytoskeletal dynamics, adhesion, and cell fate, and explore the ramifications of Shc dysregulation for malignant transformation.