Editors' ChoiceCell Cycle

“SHP”-ed Out of the Nucleus

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Sci. Signal.  16 Sep 2008:
Vol. 1, Issue 37, pp. ec324
DOI: 10.1126/scisignal.137ec324

The protein tyrosine phosphatase SHP-1 is a negative regulator of several receptor types at the cell membrane. Loss of its inhibition of mitogenic signals mediated by tyrosine phosphorylation is associated with various cancers of hematopoietic cells. Simoneau et al. argue that there may be another side to SHP-1’s personality, evident particularly in epithelial cells in which SHP-1 is primarily localized to the nucleus rather than the cytoplasm, where it is most abundant in hematopoietic cells. In these cells, SHP-1 also appears to inhibit cell cycle progression, an effect that is in turn regulated by cyclin-dependent kinase 2 (Cdk2). The authors identified Cdk2 in a yeast two-hybrid screen for proteins that interacted with full-length SHP-1. The interaction was confirmed in human intestinal epithelial cells and shown to be enhanced in proliferating cells. Cdk2 is regulated by tyrosine phosphorylation, but SHP-1 did not affect phosphorylation of Cdk2 under the conditions tested. Rather, Cdk2 appeared to regulate SHP-1. Phosphorylation of target proteins by Cdk2 often marks those proteins for degradation, and the abundance of SHP-1 was inversely correlated with the activity of Cdk2 complexes. Furthermore, pharmacological inhibition of Cdk2 or of the 20S proteasome increased the abundance of SHP-1. Proteolytic cleavage of SHP-1 produced a smaller, 45-kD fragment of SHP-1 that maintained phosphatase activity and accumulated in the cytoplasm. Thus, the authors propose that Cdk2-mediated phosphorylation of SHP-1 may dampen its inhibitory actions on proliferation in intestinal epithelial cells, perhaps also switching its biological function through cleavage and relocation outside the nucleus.

M. Simoneau, J. Boulanger, G. Coulombe, M.-A. Renaud, C. Duchesne, M. Rivard, Activation of Cdk2 stimulates proteasome-dependent truncation of tyrosine phosphatase SHP-1 in human proliferating intestinal epithelial cells. J. Biol. Chem. 283, 25544-25556 (2008). [Abstract] [Full Text]

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