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J. Biol. Chem., Vol. 279, Issue 27, 28450-28457, July 2, 2004

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The Cytoplasmic Tyrosine Kinase Pyk2 as a Novel Effector of Fibroblast Growth Factor Receptor 3 Activation^*

April N. Meyer, Randy F. Gastwirt, David D. Schlaepfer¶, and Daniel J. Donoghue||

From the Department of Chemistry and Biochemistry, Center for Molecular Genetics and the Biomedical Sciences Program, University of California San Diego, La Jolla, California 92093-0367 and the ^¶Scripps Research Institute, Department of Immunology, La Jolla, California 92037

Activating mutations within fibroblast growth factor receptor 3 (FGFR3), a receptor tyrosine kinase, are responsible for human skeletal dysplasias including achondroplasia and the neonatal lethal syndromes thanatophoric dysplasia types I and II. Several of these same FGFR3 mutations have also been identified somatically in human cancers, including multiple myeloma, bladder carcinoma, and cervical cancer. The molecular pathways exploited by FGFR3 to stimulate abnormal proliferation during neoplasia are unclear. The nonreceptor protein-tyrosine kinase Pyk2 (proline-rich tyrosine kinase 2) has been shown previously to regulate apoptosis in multiple myeloma cells. Here we describe a novel interaction between FGFR3 and Pyk2, mediated by the juxtamembrane domain of FGFR3 and the kinase domain of Pyk2. Within the FGFR family, Pyk2 also interacted significantly with FGFR2. Overexpression of Pyk2 alone led to its spontaneous activation and tyrosine phosphorylation, resulting in activation of Stat5B, indicated by the reporter GFP-Stat5B. These effects were completely dependent upon Tyr⁴⁰², the autophosphorylation site of Pyk2, which allows recruitment of Src family members for further activating phosphorylations at other sites on Pyk2. In the presence of activated FGFR3, the activation of Pyk2 itself became independent of Tyr⁴⁰², indicating that FGFR3 activation circumvents the requirement for c-Src recruitment at Tyr⁴⁰² of Pyk2. We also examined the role of the tyrosine phosphatase Shp2 in antagonizing Pyk2 activation. Taken together, these results suggest that signaling pathways regulated by FGFR3 may converge with Pyk2-dependent pathways to provide maximal activation of Stat5B.

Received for publication, March 25, 2004

This paper is dedicated to the memory of Fred F. Novell (1942–2003).

^* This work was supported by grants from National Institutes of Health Grants R01-GM65490 and R01-CA90900 (to D. J. D.) and by funds from the Multiple Myeloma Research Foundation. 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.

^|| To whom correspondence should be addressed: Dept. of Chemistry and Biochemistry, Center for Molecular Genetics, University of California San Diego, La Jolla, CA 92093-0367. Tel.: 858-534-2463; Fax: 858-534-7481; E-mail: ddonoghue{at}ucsd.edu.

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