Protein-tyrosine phosphatase SHP-1 is expressed at high levels in hematopoietic cells and at moderate levels in many other cell types including epithelial cells. Although SHP-1 has been shown to be a negative regulator of multiple signaling pathways in hematopoietic cells, very little is known about the biological role of SHP-1 in epithelial cells. In order to elucidate the mechanism(s) responsible for the loss of proliferative potential once committed intestinal epithelial cells begin to differentiate, the role and regulation of SHP-1 were analyzed in both intact epithelium as well as in well established intestinal cell models recapitulating the crypt-villus axis in vitro. Results show that SHP-1 was expressed in the nuclei of all intestinal epithelial cell models as well as in epithelial cells of intact human fetal jejunum and colon. Expression and phosphatase activity levels of SHP-1 were much more elevated in confluent growth-arrested intestinal epithelial cells and in differentiated enterocytes as well. Overexpression of SHP-1 in intestinal epithelial crypt cells significantly inhibited dhfr, c-myc, and cyclin D1 gene expression but did not interfere with c-fos gene expression. In contrast, a mutated inactive form of SHP-1 had no effect on these genes. SHP-1 expression significantly decreased beta-catenin/TCF-dependent transcription in intestinal epithelial crypt cells. Immunoprecipitation experiments revealed that beta-catenin is one of the main binding partners and a substrate for SHP-1. Taken together, our results indicate that SHP-1 may be involved in the regulation of beta-catenin transcriptional function and in the negative control of intestinal epithelial cell proliferation.

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SHP-1 is expressed in the nuclei of intestinal epithelial cells (IECs).SHP-1, an SH2 4 domain-containing protein-tyrosine phosphatase, is a key regulator in the control of intracellular levels of phosphotyrosine. It is predominantly expressed in hematopoietic cells and epithelial cells (1-3). SHP-1 contains two Src homology (SH2) domains, a neighboring catalytic domain, and a C-terminal tail. Its phosphatase activity is inhibited by the interaction between the N-terminal SH2 domain and the catalytic domain (4 -7). SHP-1 acts as a negative regulator of intracellular signaling by three families of transmembrane receptors: growth factor receptors with an intrinsic tyrosine kinase activity (e.g. c-Kit, CSF-1, TrkA, and EGF) (8 -12), cytokine receptors (e.g. Epo-R, IFN␣/␤-R, IL-3R, and IL-2R) (9 -17), and receptors involved in immune responses, such as the T-cell receptor complex, CD5, and death receptor (18 -21). SHP-1 binds the immunoreceptor tyrosine-based inhibition motif of these receptors through its SH2 domains and dephosphorylates downstream proteins. Its effect is to terminate the signal of the activated receptor or to activate other terminating pathways, such as apoptosis (22).On the other hand, very little is known as to the biological roles of SHP-1 in epithelial cells, although the existence of an epithelium-specific isoform of SHP-1 is suggestive of specific function(s) in these cells (23). Keilhack et al. (24) have previously shown that SHP-1 is an important downstream regulator of ROS signaling in epididymal epithelium. Furthermore, previous evidence indicates that SHP-1 associates with and dephosphorylates p120 catenin in EGF-stimulated A431 cells (25), suggesting a role for this PTP in the regulation of catenin function and cadherin-mediated epithelial cell-cell adhesion. Furthermore, SHP-1 localization differs between nonhematopoietic and hematopoietic cells, with SHP-1 protein being virtually exclusively cytoplasmic in hematopoietic cells and nuclear in nonhematopoietic cells (26). These results have implications regarding the nuclear function of SHP-1 in nonhematopoietic cells. Our recent data indicate that increased SHP-1 expression and activity coincide with cell cycle arrest and induction of differentiation of intestinal epithelial cells. Results show that overexpression of SHP-1 in intestinal epithelial crypt cells significantly inhibited dhfr, c-myc, and cyclin D1 gene expression and decreased ␤-catenin-T cell factor (TCF)-

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On page 25551, a Western blot for another protein (not SHP-1) was inadvertently printed in Fig. 4B. The correct figure is shown below. The results were not affected by this error. ADDITIONS AND CORRECTIONS This paper is available online at www.jbc.orgWe suggest that subscribers photocopy these corrections and insert the photocopies in the original publication at the location of the original article. Authors are urged to introduce these corrections into any reprints they distribute. Secondary (abstract) services are urged to carry notice of these corrections as prominently as they carried the original abstracts.