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Molecular and Cellular Biology, June 2003, p. 3753-3762, Vol. 23, No. 11
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.11.3753-3762.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Protein Tyrosine Phosphatase 1B Attenuates Growth Hormone-Mediated JAK2-STAT Signaling

Feng Gu,1 Nadia Dubé,1 Jin Wook Kim,2 Alan Cheng,1 Maria de Jesus Ibarra-Sanchez,1 Michel L. Tremblay,1* and Yves R. Boisclair2*

McGill Cancer Center and Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada,1 Department of Animal Science, Cornell University, Ithaca, New York 148532

Received 18 December 2002/ Returned for modification 5 February 2003/ Accepted 6 March 2003

Protein tyrosine phosphatase-1B (PTP-1B) attenuates insulin, PDGF, EGF, and IGF-I signaling by dephosphorylating tyrosine residues located in the tyrosine kinase domain of the corresponding receptors. More recently, PTP-1B was shown to modulate the action of cytokine signaling via the nonreceptor tyrosine kinase JAK2. Transmission of the growth hormone (GH) signal also depends on JAK2, raising the possibility that PTP-1B modulates GH action. Consistent with this hypothesis, GH increased the abundance of tyrosine-phosphorylated JAK2 associated with a catalytically inactive mutant of PTP-1B. GH-induced JAK2 phosphorylation was greater in knockout (KO) than in wild-type (WT) PTP-1B embryonic fibroblasts and resulted in increased tyrosine phosphorylation of STAT3 and STAT5, while overexpression of PTP-1B reduced the GH-mediated activation of the acid-labile subunit gene. To evaluate the in vivo relevance of these observations, mice were injected with GH under fed and fasted conditions. As expected, tyrosine phosphorylation of JAK2 and STAT5 occurred readily in the livers of fed WT mice and was almost completely abolished during fasting. In contrast, resistance to the action of GH was severely impaired in the livers of fasted KO mice. These results indicate that PTP-1B regulates GH signaling by reducing the extent of JAK2 phosphorylation and suggest that PTP-1B is essential for limiting the action of GH during metabolic stress such as fasting.

* Corresponding author. Mailing address for M. L. Tremblay: McGill Cancer Center, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec H3G 1Y6, Canada. Phone: (514) 398-8480. Fax: (514) 398-6769. E-mail: michel.tremblay{at}mcgill.ca. Mailing address for Y. R. Boisclair: Department of Animal Science, Cornell Uiversity, 259 Morrison Hall, Ithaca, NY 14853-4801. Phone: (607) 254-4704. Fax: (607) 255-9829. E-mail: yrb1{at}cornell.edu.

Molecular and Cellular Biology, June 2003, p. 3753-3762, Vol. 23, No. 11
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.11.3753-3762.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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