PTP-kappa and PTP SHP-1 are involved in the regulation of cell-cell contacts at adherens junctions in the exocrine pancreas

Juergen Schnekenburger ¹, Julia Mayerle ², Burkhard Krueger ³, Igor Buchwalow ¹, Frank U Weiss ², Elke Albrecht ⁴, Very Samoilova ¹, Wolfram Domschke ¹ and Markus M. Lerch ^2*

¹ Department of Medicine B, University of Muenster, Germany
² Department of Medicine A, University of Greifswald, Germany
³ Dept. of Pathology, University of Rostock, Germany
⁴ Division of Medical Biology, Department of Pathology, University of Rostock, Germany

^* To whom correspondence should be addressed. E-mail: lerch{at}uni-greifswald.de.

Accepted 12 April 2005

Abstract

Backround: We have previously shown that cell- contacts between pancreatic acinar cells dissociate early in pancreatitis and that this is a prerequisite for the development of pancreatic edema. Here we studied the underlying mechanism.

Methods: Employing experimental caerulein-induced pancreatitis in vivo and isolated pancreatic acini ex vivo in conjunction with protein chemistry, morphology and electronmicroscopy we determined whether cell-contact regulation in the pancreas requires or involves: 1) changes in cadherin/catenin protein expression, 2) tyrosine phosphorylation of adhesion proteins and 3) alterations in the actin cytoskeleton.

Results: During initial cell-cell contact dissociation at adherens junctions the expression of adhesion proteins remained stable. At time points of dissociated adherens junctions the cadherin/catenin complex was found to be tyrosine phosphorylated and internalized. The receptor type protein tyrosine phosphatase PTP kappa was constitutively associated with the cadherin/catenin complex at intact cell contacts whereas, following the dissociation of adherens junctions, the internalized components of the cadherin/catenin complex were tyrosine phosphorylated and associated with the cytosolic protein tyrosine phosphatase PTP SHP-1. In isolated acini inhibition of endogenous protein tyrosine phosphatases alone was sufficient to induce a dissociation of adherens junctions analogous to that found with supramaximal caerulein stimulation. Dissociation of actin microfilaments had no effect on adherens junction integrity.

Conclusions: These data identify tyrosine phosphorylation as the key regulator for cell contacts at adherens junctions and suggest a definitive role for the protein tyrosine phosphatases PTP kappa and SHP-1 in the regulation, maintenance and restitution of cell adhesions in a complex epithelial organ such as the pancreas.

Keywords: cadherin-catenin complex, orthovanadate, pancreatitis, protein tyrosine phosphatases, tyrosine phosphorylation

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