Compartmentalized Ras/Mapk Signaling

Abstract

Signal transduction down the Ras/MAPK pathway, including that critical to T cell activation, proliferation, and differentiation, has been generally considered to occur at the plasma membrane. It is now clear that the plasma membrane does not represent the only platform for Ras/MAPK signaling. Moreover, the plasma membrane itself is no longer considered a uniform structure but rather a patchwork of microdomains that can compartmentalize signaling. Signaling on internal membranes was first recognized on endosomes. Genetically encoded fluorescent probes for signaling events such as GTP/GDP exchange on Ras have revealed signaling on a variety of intracellular membranes, including the Golgi apparatus. In fibroblasts, Ras is activated on the plasma membrane and Golgi with distinct kinetics. The pathway by which Golgi-associated Ras becomes activated involves PLCgamma and RasGRP1 and may also require retrograde trafficking of Ras from the plasma membrane to the Golgi as a consequence of depalmitoylation. Thus, the Ras/MAPK pathway represents a clear example of compartmentalized signaling.

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“…Distinct functional pools of ERK are hypothesized to be defined by outcome-specific scaffolds that couple ERK activation and/or function to select downstream targets in a spatially and temporally restricted manner [124,125]. Our recent observations have suggested a potential role for the MP1-p14 complex in coupling MAP kinase signaling to Rho [126].…”

“…First, dominant-negative dynamin inhibits ERK activation in response to many receptor tyrosine kinase and G-protein coupled ligands [149], and much evidence indicates that ERK signaling continues on endosomes internalized following receptor stimulation [124]. Interestingly however, Moolenaar and colleagues [149] determined that internalization of a plasma membrane receptor per se was not required for dynamin's effect on ERK activation, since phorbol ester stimulated activation of ERK was also blocked by dominant-negative dynamin.…”

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