A Scaffold for Interactions

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Science  07 Aug 2009:
Vol. 325, Issue 5941, pp. 656-657
DOI: 10.1126/science.325_656c

The mitogen-activated protein kinase (MAPK) signaling pathway provides an example of the elaborate controls that are necessary when a cellular module regulates a huge range of processes from proliferation and survival to metabolism and cell motility. The enzymes of the MAPK cascade—the protein kinase Raf, which phosphorylates the kinase MEK, which in turn phosphorylates the MAPK ERK—are localized in complexes by scaffold proteins, increasing the efficiency of interactions and stipulating the specificity of such events. McKay et al. have established the intricate choreography of interactions mediated by the scaffold protein KSR1. This protein was identified as a positive regulator of the small guanosine triphosphatase Ras, which initiates the activation of Raf and the rest of the MAPK cascade. KSR1 forms a ternary complex with Raf and MEK; this activates ERK, and the activation of ERK exposes a site that allows ERK to bind to KSR1, where it (ERK, that is) phosphorylates four sites each on KSR1 and Raf. When the binding site for ERK on KSR1 was disrupted or the sites that ERK phosphorylates on KSR1 were removed, though, the interaction of KSR with Raf1 was enhanced and signaling was prolonged. Thus, the authors conclude that ERK provides a negative-feedback signal that disrupts interaction of Raf and KSR1 and releases KSR1 from the cell membrane, thereby adjusting the intensity and duration of signaling through the MAPK cascade.

Proc. Natl. Acad. Sci. U.S.A. 106, 11022 (2009).

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