Abstract
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.
Highlights
Protein phosphorylation and dephosphorylation of tyrosyl residues are important events involved in the regulation of cell growth and differentiation
Our results indicate that SHP-1 negatively regulates -catenin-dependent transcriptional activity resulting in the inhibition of cyclin D1 and c-myc gene expression, the activation of which represents one of the earliest cell cycle-regulated events occurring during the transition from G0/G1 to S phase
The use of a specific antibody against SHP-1 revealed that this Protein-tyrosine phosphatases (PTPs) was expressed in the nuclei of all jejunal and colonic epithelial cells (Fig. 1, A and B), with strongest nuclear staining observed in cells occupying the lower third of the villus in the jejunum (Fig. 1A, see arrows) and the mid-region of colonic crypts (Fig. 1B, see arrowheads)
Summary
Protein phosphorylation and dephosphorylation of tyrosyl residues are important events involved in the regulation of cell growth and differentiation. Our results indicate that SHP-1 may be involved in the regulation of -catenin transcriptional function and in the negative control of intestinal epithelial cell proliferation.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
