ERK Activation Pathways Downstream of GPCRs

GPCRs, the 7-TM receptors, represent a class of cell surface receptors which modulate a variety of physiological responses. The serpentine structure in addition to contributing the diversity of stimuli these receptors can sense also provides flexibility to the extracellular and intracellular regions where other proteins can interact with and can form functionally active multimeric entities. The range in signaling and physiological responses generated by these receptors can be attributed to a large repertoire of the receptor subtypes as well as their differential coupling to various classes of G-protein subunits and other proteins which facilitate multistate activation. A multistate GPCR can engage diverse signaling molecules, thereby modulating not only the canonical cellular responses but also noncanonical responses typically associated with activation of other cascades such as RTK and MAPK/ERK signaling. Given the crucial involvement of MAP kinase/ERK signaling in cell fate determination specially with respect to regulating cell proliferation, cellular apoptosis, and survival, GPCR-mediated cross-activation of MAPK has been explored in various systems and shown to involve functional integration of multiple pathways. This review describes the present knowledge of the different mechanisms of ERK activation downstream of GPCRs and our present understanding of receptor-dependent and -independent MAPK activation cascades