Regulation of MAPKs by growth factors and receptor tyrosine kinases

Multiple growth- and differentiation-inducing polypeptide factors bind to and activate transmembrane receptors tyrosine kinases (RTKs), to instigate a plethora of biochemical cascades culminating in regulation of cell fate. We concentrate on the four linear mitogen-activated protein kinase (MAPK) cascades, and highlight organizational and functional features relevant to their action downstream to RTKs. Two cellular outcomes of growth factor action, namely proliferation and migration, are critically regulated by MAPKs and we detail the underlying molecular mechanisms. Hyperactivation of MAPKs, primarily the Erk pathway, is a landmark of cancer. We describe the many links of MAPKs to tumor biology and review studies that identified machineries pennitting prolongation of MAPK signaling. Models attributing signal integration to both phosphorylation of MAPK substrates and to MAPK-regulated gene expression may shed light on the remarkably diversified functions of MAPKs acting downstream to activated RTKs. (C) 2007 Elsevier B.V. All rights reserved.