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JCS ePress online publication date 22 Feb 2005
doi: 10.1242/jcs.01679

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Research Article

Cbl-mediated ubiquitination of {alpha}5 integrin subunit mediates fibronectin-dependent osteoblast detachment and apoptosis induced by FGFR2 activation


Karim Kaabeche, Hind Guenou, Daniel Bouvard, Nadège Didelot, Antoine Listrat, and Pierre J. Marie*
* Author for correspondence (e-mail: pierre.marie{at}larib.inserm.fr)

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 {alpha}5 integrin subunit normally expressed in human calvarial osteoblasts in vivo. Treatment with lactacystin, a potent inhibitor of proteasome, restored {alpha}5 integrin levels in FGFR2 mutant osteoblasts. Immunoprecipitation analysis showed that {alpha}5 integrin interacts with both the E3 ubiquitin ligase Cbl and ubiquitin. Immunocytochemistry revealed that {alpha}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 {alpha}5 integrin levels. This suggests that Cbl-mediated ubiquitination plays an essential role in {alpha}5 integrin proteasome degradation induced by FGFR2 activation. Reduced {alpha}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 {alpha}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 {alpha}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 {alpha}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 {alpha}5 integrin degradation.


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