Editors' ChoiceDevelopment

Working It Out Downstream

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Science's STKE  01 Dec 1999:
Vol. 1999, Issue 10, pp. tw6
DOI: 10.1126/stke.1999.10.tw6

A cell's response to a particular growth factor or hormone involves a relay of signals between the cell surface and the nucleus. The small GTP-binding protein Ras is activated by numerous growth factor receptors and can regulate more than one signaling pathway in response to a single growth factor, depending on the cell type. Hence, Ras can serve as a branch point for signal propagation, and tight regulation of the pathways it stimulates is needed to ensure the proper biological outcome. Two reports describe the cross-communication that occurs between two pathways that lie downstream of Ras, the Raf kinase-MEK (mitogen-activated protein kinase)-ERK (extracellular-regulated kinase) pathway and the PI3K (phosphatidylinositol 3-kinase)-Akt kinase pathway. Zimmermann and Moelling demonstrate that Akt inhibited Raf activity by phosphorylating a known regulatory site on Raf. In breast cancer cells, Akt directly interacted with Raf, and inhibition of Akt resulted in increased Raf activity. The authors suggest that in these cells, this mechanism may regulate growth response to insulin-like growth factor (IGF). Rommel et al. also reveal that Akt associated with Raf and inhibited the Raf signaling pathway in differentiated muscle cells (myotubes) but not in undifferentiated precursor cells. Activation of the Akt pathway or inhibition of the Raf pathway resulted in a hypertrophic phenotype (thickening) similar to that induced by IGF on muscle cells. These studies suggest that integration of these two pathways into a particular cellular response may depend on cell type or the stage of cell differentiation.

Zimmermann, S., and Moelling, K. (1999) Phosphorylation and regulation of Raf by Akt (protein kinase B) Science 286: 1741-1744. [Abstract] [Full Text]

Rommel, C., Clarke, B.A., Zimmermann, S., Nuñez, L., Rossman, R., Reid, K., Moelling, K., Yancopoulos, G.D., and Glass, D.J. (1999) Differentiation stage-specific inhibition of the Raf-MEK-ERK Pathway by Akt. Science 286: 1738-1741. [Abstract] [Full Text]

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