Recent advances in Ca 2+-dependent Ras regulation and cell proliferation

Abstract

Our understanding of the mechanisms whereby growth factors stimulate cell proliferation through the Ras pathway stems largely from studies of the canonical pathway involving recruitment of Ras activators and inhibitors to the vicinity of receptor tyrosine kinases via phosphotyrosine-binding adaptor proteins. Ca 2+ has seldom joined the party, despite the identification of phospholipase Cγ and Ca 2+ entry as receptor tyrosine kinase-dependent signals. Mechanisms by which Ca 2+ can directly influence Ras activity have remained relatively elusive. Similarly, the mechanisms whereby Ca 2+ modulates the cell cycle have been equally murky, and yet there are some interesting parallels in the role of Ras and Ca 2+ in cell cycle re-entry. This review focuses on a number of novel mechanisms that link Ca 2+ with the regulation of Ras activity and signaling output. Their collective discovery adds to the complexities of Ras regulation and raises further questions about the role of Ca 2+ signals in Ras-dependent cell proliferation.