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Molecular and Cellular Biology, May 2006, p. 3917-3934, Vol. 26, No. 10
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.10.3917-3934.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Furin-, ADAM 10-, and {gamma}-Secretase-Mediated Cleavage of a Receptor Tyrosine Phosphatase and Regulation of ß-Catenin's Transcriptional Activity{dagger}

Lars Anders,1,{ddagger}* Philipp Mertins,1,{ddagger} Sven Lammich,2 Marta Murgia,1,§ Dieter Hartmann,3 Paul Saftig,4 Christian Haass,2 and Axel Ullrich1*

Department of Molecular Biology, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany,1 Laboratory for Alzheimer's and Parkinson's Disease Research, Department of Biochemistry, Adolf Butenandt Institute, Ludwig Maximilians University, 80336 Muenchen, Germany,2 Department of Human Genetics, KU Leuven and Flanders Interuniversity Institute for Biotechnology (VIB-4), 3000 Leuven, Belgium,3 Institute of Biochemistry, Christian Albrechts University, 24118 Kiel, Germany,4 4

Received 20 July 2005/ Returned for modification 19 August 2005/ Accepted 8 February 2006

Several receptor protein tyrosine phosphatases (RPTPs) are cell adhesion molecules involved in homophilic interactions, suggesting that RPTP outside-in signaling is coupled to cell contact formation. However, little is known about the mechanisms by which cell density regulates RPTP function. We show that the MAM family prototype RPTP{kappa} is cleaved by three proteases: furin, ADAM 10, and {gamma}-secretase. Cell density promotes ADAM 10-mediated cleavage and shedding of RPTP{kappa}. This is followed by {gamma}-secretase-dependent intramembrane proteolysis of the remaining transmembrane part to release the phosphatase intracellular portion (PIC) from the membrane, thereby allowing its translocation to the nucleus. When cells were treated with leptomycin B, a nuclear export inhibitor, PIC accumulated in nuclear bodies. PIC is an active protein tyrosine phosphatase that binds to and dephosphorylates ß-catenin, an RPTP{kappa} substrate. The expression of RPTP{kappa} suppresses ß-catenin's transcriptional activity, whereas the expression of PIC increases it. Notably, this increase required the phosphatase activity of PIC. Thus, both isoforms have acquired opposing roles in the regulation of ß-catenin signaling. We also found that RPTPµ, another MAM family member, undergoes {gamma}-secretase-dependent processing. Our results identify intramembrane proteolysis as a regulatory switch in RPTP{kappa} signaling and implicate PIC in the activation of ß-catenin-mediated transcription.

* Corresponding author. Present address for Lars Anders: Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Pathology, Harvard Medical School, 44 Binney Street, Boston, MA 02115. Phone: (617) 632-4311. Fax: (617) 632-5006. E-mail: lars_anders{at}dfci.harvard.edu. Mailing address for Axel Ullrich: Department of Molecular Biology, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany. Phone: 49 89 8578 2512. Fax: 49 89 8578 2454. E-mail: ullrich{at}biochem.mpg.de.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} These authors contributed equally to this work.

§ Present address: Department of Biomedical Sciences, Consiglio Nationale delle Ricerche Center of Muscle Biology and Physiopathology, University of Padova, 35121 Padova, Italy.

Molecular and Cellular Biology, May 2006, p. 3917-3934, Vol. 26, No. 10
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.10.3917-3934.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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