Recent advances in Ca2+-dependent Ras regulation and cell proliferation

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. Ca2+ has seldom joined the party, despite the identification of phospholipase Cγ and Ca2+ entry as receptor tyrosine kinase-dependent signals. Mechanisms by which Ca2+ can directly influence Ras activity have remained relatively elusive. Similarly, the mechanisms whereby Ca2+ modulates the cell cycle have been equally murky, and yet there are some interesting parallels in the role of Ras and Ca2+ in cell cycle re-entry. This review focuses on a number of novel mechanisms that link Ca2+ 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 Ca2+ signals in Ras-dependent cell proliferation.