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First published online 22 February 2005
doi: 10.1242/jcs.01679
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Research Article |
5 integrin subunit mediates fibronectin-dependent osteoblast detachment and apoptosis induced by FGFR2 activation
1 INSERM U 606, Lariboisière Hospital, 2 rue Ambroise Paré, 75010 Paris, Université Paris 7, Paris, France
2 LEDAC, UMR CNRS/UJF 5538, Institut Albert Bonniot, Faculté de Médecine, 38706 La Tronche CEDEX, France
* Author for correspondence (e-mail: pierre.marie{at}larib.inserm.fr)
Accepted 8 December 2004
Fibroblast growth factor receptor signaling is an important mechanism regulating osteoblast function. To gain an insight into the regulatory role of FGF receptor-2 (FGFR2) signaling in osteoblasts, we investigated integrin-mediated attachment and cell survival in human calvarial osteoblasts expressing activated FGFR2. FGFR2 activation reduced osteoblast attachment on fibronectin. This was associated with reduced expression of the 
5 integrin subunit normally expressed in human calvarial osteoblasts in vivo. Treatment with lactacystin, a potent inhibitor of proteasome, restored 5 integrin levels in FGFR2 mutant osteoblasts. Immunoprecipitation analysis showed that 5 integrin interacts with both the E3 ubiquitin ligase Cbl and ubiquitin. Immunocytochemistry revealed that 5 integrin colocalizes with FGFR2 and Cbl at the leading edge in membrane ruffle regions. Transfection with the 70Z-Cbl mutant lacking the RING domain required for Cbl-ubiquitin interaction, or with the G306E Cbl mutant that abolishes the binding ability of Cbl phosphotyrosine-binding domain restored 5 integrin levels. This suggests that Cbl-mediated ubiquitination plays an essential role in 5 integrin proteasome degradation induced by FGFR2 activation. Reduced 5 integrin expression was associated with an increased Bax/Bcl-2 ratio and increased caspase-9 and -3 activities in FGFR2 mutant osteoblasts. Forced expression of 5 integrin rescued cell attachment and corrected both the Bax/Bcl-2 ratio and caspase-3 and caspase-9 activities in FGFR2 mutant osteoblasts. We show that Cbl recruitment induced by FGFR2 activation triggers 5 integrin degradation by the proteasome, which results in reduced osteoblast attachment on fibronectin and caspase-dependent apoptosis. This identifies a functional role of the 5 integrin subunit in the induction of apoptosis triggered by FGFR2 activation in osteoblasts, and reveals that a Cbl-dependent mechanism is involved in the coordinated regulation of cell apoptosis induced by 5 integrin degradation.
Key words: Osteoblast, 5 integrin, FGFR2, Cbl, Apoptosis, Ubiquitination
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