GROWTH FACTORS MAP Kinase-Induced Cleavage

Abstract: Transmembrane-type growth factors, such as transforming growth factor– (TGF-), can exert their effects locally on neighboring cells, or at a distance if they are cleaved from the cell surface. This shedding process is thought to be mediated by cell surface metalloproteases. However, the signaling mechanisms that regulate this process are unclear. Fan and Derynck suggest that cell surface cleavage of a variety of transmembrane proteins may be regulated by the activation of receptor tyrosine kinases. Treatment of cells with mitogenic growth factors such as epidermal growth factor and platelet-derived growth factor induced cleavage of transmembrane TGF- and release of soluble TGF-. Inhibiting the Ras-Raf-MEK-Erk pathway with specific inhibitors or overexpression of dominant-negative mutants blocked this effect. The authors also found that in the absence of growth factor stimulation, a basal level of TGF- ectodomain shedding occurred through a p38 MAP kinase–dependent pathway. These results suggest that activation of p38 controls a basal release of TGF-, and growth factor stimulation induces release through Erk. This may be a general mechanism in that shedding of the transmembrane proteins tumor necrosis factor- and L-selectin were also regulated similarly. How the MAP kinase pathways activate proteases has yet to be determined.

Fan, H., and Derynck, R. (1999) Ectodomain shedding of TGF- and other transmembrane proteins is induced by receptor tyrosine kinase activation and MAP kinase signaling cascades. EMBO J. 18: 6962-6972. [Abstract] [Full Text]