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J. Biol. Chem., Vol. 279, Issue 35, 36259-36267, August 27, 2004

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Cbl-mediated Degradation of Lyn and Fyn Induced by Constitutive Fibroblast Growth Factor Receptor-2 Activation Supports Osteoblast Differentiation^*

Karim Kaabeche, Jérome Lemonnier¶, Sandrine Le Mée, Joseph Caverzasio¶, and Pierre J. Marie||

From the Laboratory of Osteoblast Biology and Pathology, INSERM U606, University Paris 7, Hôpital Lariboisière, 75475 Paris Cedex 10, France and the ^¶Service of Bone Diseases, CH-1211 Geneva 14, Switzerland

Fibroblast growth factors (FGFs) play an important regulatory role in skeletal development and bone formation. However, the FGF signaling mechanisms controlling osteoblast function are poorly understood. Here, we identified a role for the Src family members Lyn and Fyn in osteoblast differentiation promoted by constitutive activation of FGF receptor-2 (FGFR2). We show that the overactive FGFR2 S252W mutation induced decreased Src family kinase tyrosine phosphorylation and activity associated with decreased Lyn and Fyn protein expression in human osteoblasts. Pharmacological stimulation of Src family kinases or transfection with Lyn or Fyn vectors repressed alkaline phosphatase (ALP) up-regulation induced by overactive FGFR2. Inhibition of proteasome activity restored normal Lyn and Fyn expression and ALP activity in FGFR2 mutant osteoblasts. Immunoprecipitation studies showed that Lyn, Fyn, and FGFR2 interacted with the ubiquitin ligase c-Cbl and ubiquitin. Transfection with c-Cbl in which the RING finger was disrupted or with c-Cbl with a point mutation that abolishes the binding ability of the Cbl phosphotyrosine-binding domain restored Src kinase activity and Lyn, Fyn, and FGFR2 levels and reduced ALP up-regulation in mutant osteoblasts. Thus, constitutive FGFR2 activation induces c-Cbl-dependent Lyn and Fyn proteasome degradation, resulting in reduced Lyn and Fyn kinase activity, increased ALP expression, and FGFR2 down-regulation. This reveals a common Cbl-mediated negative feedback mechanism controlling Lyn, Fyn, and FGFR2 degradation in response to overactive FGFR2 and indicates a role for Cbl-dependent down-regulation of Lyn and Fyn in osteoblast differentiation induced by constitutive FGFR2 activation.

Received for publication, March 4, 2004 , and in revised form, June 2, 2004.

^* 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.

Recipient of a scholarship from the Ministère de la Recherche et de la Technologie (France).

^|| To whom correspondence should be addressed: Lab. of Osteoblast Biology and Pathology, INSERM U606, Hôpital Lariboisière, 2 rue Ambroise Paré, 75475 Paris Cedex 10, France. Tel.: 33-1-4995-6389; Fax: 33-1-4995-8452; E-mail: pierre.marie{at}larib.inserm.fr.

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