Modulation of the Ras/Raf/MEK/ERK pathway by Ca2+, and calmodulin

Ras activation induces a variety of cellular responses that depend on the specific activated effector, the intensity and amplitude of its activation, and the cellular type. Transient activation followed by a sustained but low signal of the Ras/Raf/MEK/ERK pathway is a common feature of cell proliferation in many systems. On the contrary, sustained, high activation is linked with either senescence or apoptosis ill fibroblasts and to differentiation in neurones and PC 12 cells. The temporal regulation of the pathway is relevant and not only depends oil the specific receptor activated but also on the presence of diverse modulators of the pathway. We review here evidence showing that calcium (Ca2+) and calmodulin (CaM) are able to regulate the Ras/Raf/MEK/ERK pathway. CaM-binding proteins (CaMBPs) as Ras-GRF and CaM-dependent protein kinase IV (CaMKIV) positively modulate ERK1/2 activation induced by either NGF or membrane depolarisation in neurotics. In fibroblasts, CaM binding to EGF receptor and K-Ras(B) may be involved ill the downregulation of the pathway after its activation, allowing a proliferative signalling. (C) 2002 Elsevier Science Inc. All rights reserved.