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This Article Accepted manuscript (PDF) All Versions of this Article: JOE-07-0262v1 197/3/543    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Welters, H. Articles by Morgan, N. PubMed PubMed Citation Articles by Welters, H. Articles by Morgan, N.

H Welters, Institute of Biomedical and Clinical Science , Peninsula Medical School, Plymouth, PL6 8BU, United Kingdom
A Oknianska, Institute of Biomedical and Clinical Science, Peninsula Medical School, Plymouth, United Kingdom
K Erdmann, Department of Biochemistry II, Ruhr-University Bochum, Bochum, Germany
G Ryffel, Institut fuer Zellbiologie (Tumorforschung), Universitaetsklinikum Essen, Essen, Germany
N Morgan, Institute of Biomedical and Clinical Science, Peninsula Medical School, Plymouth, United Kingdom

Correspondence: Hannah Welters, Email: hannah.welters{at}pms.ac.uk

Abstract

In pancreatic beta-cells, increased expression of the MODY5 gene product, HNF1β, leads to enhanced rates of apoptosis and altered regulation of the cell cycle suggesting that control of HNF1β expression may be important for the control of β-cell proliferation and viability. It is unclear how these effects of HNF1β are mediated but previously, we identified a protein tyrosine phosphatase, PTP-BL, as an HNF1β-regulated protein in β-cells and we have now studied the role of this protein in INS-1 β-cells. Stably transfected cells were generated that express either wild type (WT) or a phosphatase-deficient mutant (PTP-BL-CS) of PTP-BL conditionally under the control of a tetracycline-regulated promoter. Enhanced expression of WT PTP-BL inhibited INS-1 cell growth dose-dependently but this effect was not observed when PTP-BL-CS was expressed. Neither construct altered the rate of apoptosis. PTP-BL has been reported to interact with components of the Wnt signalling pathway and we observed that addition of exogenous Wnt3a resulted in a rise in β-catenin levels and an increase in cell proliferation, consistent with the operation of this pathway in INS-1 cells. Up-regulation of WT PTP-BL antagonised these responses to Wnt3a but PTP-BL-CS failed to inhibit Wnt3a-induced proliferation. The rise in β-catenin caused by Wnt3a was also suppressed by over-expression of HNF1β, suggesting that HNF1β may interact with the Wnt signalling pathway via an increase in PTP-BL levels. We conclude that PTP-BL plays an important role in regulation of cell cycle progression in pancreatic β-cells and that it interacts functionally with components of the Wnt signalling pathway.