Negative regulation of beta-catenin signaling by tyrosine phosphatase SHP-1 in intestinal epithelial cells.

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.