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J. Biol. Chem., Vol. 282, Issue 48, 35405-35415, November 30, 2007

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Protein-tyrosine Phosphatase H1 Controls Growth Hormone Receptor Signaling and Systemic Growth^*

Iwona Pilecka¹, Claudia Patrignani, Rosanna Pescini, Marie-Laure Curchod, Dominique Perrin, Yingzi Xue^¶, Jason Yasenchak^¶, Ann Clark^||, Maria Chiara Magnone², Paola Zaratin, David Valenzuela^¶, Christian Rommel, and Rob Hooft van Huijsduijnen³

From the Merck Serono International, 1211 Geneva, Switzerland, Merck Serono Istituto di Ricerche Biomediche "Antoine Marxer" (RBM), Colleretto Giacosa (TO) 10010, Italy, ^¶Regeneron Pharmaceuticals, Inc. Tarrytown, New York 10591-6707, and ^||EMD Serono Research Institute, Rockland, Massachusetts 02370

Several protein-tyrosine phosphatases (PTPs) have been implicated in the control of growth hormone receptor (GHR) signaling, but none have been shown to affect growth in vivo.We have applied a battery of molecular and cellular approaches to test a family-wide panel of PTPs for interference with GHR signaling. Among the subset of PTPs that showed activity in multiple readouts, we selected PTP-H1/PTPN3 for further in vivo studies and found that mice lacking the PTP-H1 catalytic domain show significantly enhanced growth over their wild type littermates. In addition, PTP-H1 mutant animals had enhanced plasma and liver mRNA expression of insulin-like growth factor 1, as well as increased bone density and mineral content. These observations point to a controlling role for PTP-H1 in modulating GHR signaling and systemic growth through insulin-like growth factor 1 secretion.

Received for publication, July 16, 2007 , and in revised form, September 4, 2007.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains additional supplemental experimental protocols, figures, and results.

¹ Present address: International Institute of Molecular and Cell Biology, 02-109 Warsaw, Poland.

² Present address: Novartis Pharma AG, Basel CH-4002, Switzerland.

³ To whom correspondence should be addressed: Merck Serono International S.A., 9, chemin des Mines, 1211 Geneva, Switzerland. Tel.: 41-22-414-3000; Fax: 41-22-794-6965; E-mail: rob.hooft{at}merckserono.net.

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