Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

J. Biol. Chem. 283 (37): 25544-25556

© 2008 by The American Society for Biochemistry and Molecular Biology, Inc.

Activation of Cdk2 Stimulates Proteasome-dependent Truncation of Tyrosine Phosphatase SHP-1 in Human Proliferating Intestinal Epithelial Cells*

Mélanie Simoneau, Jim Boulanger, Geneviève Coulombe1, Marc-André Renaud1, Cathia Duchesne2, , and Nathalie Rivard, Recipient of a Canadian Research Chair in Signaling and Digestive Physiopathology3

Département d'Anatomie et Biologie Cellulaire, Faculté de Médecine et des Sciences de la Santé, Universitéde Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada

Abstract: SHP-1 is expressed in the nuclei of intestinal epithelial cells (IECs). Increased SHP-1 expression and phosphatase activity coincide with cell cycle arrest and differentiation in these cells. Suspecting the tumor-suppressive properties of SHP-1, a yeast two-hybrid screen of an IEC cDNA library was conducted using the full-length SHP-1 as bait. Characterization of many positive clones revealed sequences identical to a segment of the Cdk2 cDNA sequence. Interaction between SHP-1 and Cdk2 was confirmed by co-immunoprecipitations whereby co-precipitated Cdk2 phosphorylated SHP-1 protein. Inhibition of Cdk2 (roscovitine) or proteasome (MG132) was associated with an enhanced nuclear punctuate distribution of SHP-1. Double labeling localization studies with signature proteins of subnuclear domains revealed a co-localization between the splicing factor SC35 and SHP-1 in bright nucleoplasmic foci. Using Western blot analyses with the anti-SHP-1 antibody recognizing the C terminus, a lower molecular mass species of 45 kDa was observed in addition to the full-length 64–65-kDa SHP-1 protein. Treatment with MG132 led to an increase in expression of the full-length SHP-1 protein while concomitantly leading to a decrease in the levels of the lower mass 45-kDa molecular species. Further Western blots revealed that the 45-kDa protein corresponds to the C-terminal portion of SHP-1 generated from proteasome activity. Mutational analysis of Tyr208 and Ser591 (a Cdk2 phosphorylation site) residues on SHP-1 abolished the expression of the amino-truncated 45-kDa SHP-1 protein. In conclusion, our results indicate that Cdk2-associated complexes, by targeting SHP-1 for proteolysis, counteract the ability of SHP-1 to block cell cycle progression of IECs.

Received for publication May 30, 2008. Revision received June 25, 2008.

* This work was supported by a grant from the Natural Sciences and Engineering Research Council of Canada (to N. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Student scholar from the Natural Sciences and Engineering Research Council of Canada.

2 Student scholar from the Fonds pour la Recherche en Santé du Québec.

3 To whom correspondence should be addressed: Dépt. d'Anatomie et de Biologie Cellulaire, Facultéde Médecine, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada. Fax: 819-564-5320; E-mail: Nathalie.Rivard{at}

High NaCl-induced inhibition of PTG contributes to activation of NFAT5 through attenuation of the negative effect of SHP-1.
X. Zhou, H. Wang, M. B. Burg, and J. D. Ferraris (2013)
Am J Physiol Renal Physiol 305, F362-F369
   Abstract »    Full Text »    PDF »
The Phosphatase Src Homology Region 2 Domain-Containing Phosphatase-1 Is an Intrinsic Central Regulator of Dendritic Cell Function.
I. R. Ramachandran, W. Song, N. Lapteva, M. Seethammagari, K. M. Slawin, D. M. Spencer, and J. M. Levitt (2011)
J. Immunol. 186, 3934-3945
   Abstract »    Full Text »    PDF »
Down-regulation of Protein-tyrosine Phosphatases Activates an Immune Receptor in the Absence of Its Translocation into Lipid Rafts.
P. Heneberg, L. Draberova, M. Bambouskova, P. Pompach, and P. Draber (2010)
J. Biol. Chem. 285, 12787-12802
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882