Cellular Redistribution of Protein Tyrosine Phosphatases LAR and PTP{sigma} by Inducible Proteolytic Processing

doi:10.1083/jcb.138.3.681

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© The Rockefeller University Press, 0021-9525/1997//681 $5.00
The Journal of Cell Biology, Volume 138, Number 3, , 1997 681-696

Article

Cellular Redistribution of Protein Tyrosine Phosphatases LAR and PTP ${sigma}$ by Inducible Proteolytic Processing

Babette Aicher, Markus M. Lerch, Thomas Müller, James Schilling, and Axel Ullrich

Department of Molecular Biology, Max-Planck-Institut für Biochemie, 82152 Martinsried, Germany

Most receptor-like protein tyrosine phosphatases (PTPases) displaya high degree of homology with cell adhesion molecules in theirextracellular domains. We studied the functional significanceof processing for the receptor-like PTPases LAR and PTP ${sigma}$ . PTP ${sigma}$ biosynthesis and intracellular processing resembled that ofthe related PTPase LAR and was expressed on the cell surfaceas a two-subunit complex. Both LAR and PTP ${sigma}$ underwent furtherproteolytical processing upon treatment of cells with eithercalcium ionophore A23187 or phorbol ester TPA. Induction of LAR processing by TPA in 293 cells did require overexpressionof PKC ${alpha}$ . Induced proteolysis resulted in shedding of the extracellulardomains of both PTPases. This was in agreement with the identificationof a specific PTP ${sigma}$ cleavage site between amino acids Pro₈₂₁ and Ile₈₂₂. Confocal microscopy studies identified adherensjunctions and desmosomes as the preferential subcellular localizationfor both PTPases matching that of plakoglobin. Consistent withthis observation, we found direct association of plakoglobinand β-catenin with the intracellular domain of LAR invitro. Taken together, these data suggested an involvementof LAR and PTP ${sigma}$ in the regulation of cell contacts in concertwith cell adhesion molecules of the cadherin/catenin family.After processing and shedding of the extracellular domain, the catalytically active intracellular portions of both PTPaseswere internalized and redistributed away from the sites ofcell–cell contact, suggesting a mechanism that regulatesthe activity and target specificity of these PTPases. Calciumwithdrawal, which led to cell contact disruption, also resultedin internalization but was not associated with prior proteolyticcleavage and shedding of the extracellular domain. We concludethat the subcellular localization of LAR and PTP ${sigma}$ is regulatedby at least two independent mechanisms, one of which requiresthe presence of their extracellular domains and one of whichinvolves the presence of intact cell–cell contacts.

Abbreviations used in this paper: GST, glutathione-S-transferase; PTPase, protein tyrosine phophatase.

Please address all correspondence to Axel Ullrich, Departmentof Molecular Biology, Max-Planck-Institut für Biochemie,Am Klopferspitz 18A, 82152 Martinsried, Germany. Tel.: (49)89-8578-2513; Fax: (49) 89-857-7866.

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