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Treatment with lactacystin, a potent inhibitor of proteasome, restored \u03b15 integrin levels in FGFR2 mutant osteoblasts. Immunoprecipitation analysis showed that \u03b15 integrin interacts with both the E3 ubiquitin ligase Cbl and ubiquitin. Immunocytochemistry revealed that \u03b15 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 \u03b15 integrin levels. This suggests that Cbl-mediated ubiquitination plays an essential role in \u03b15 integrin proteasome degradation induced by FGFR2 activation. Reduced \u03b15 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 \u03b15 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 \u03b15 integrin degradation by the proteasome, which results in reduced osteoblast attachment on fibronectin and caspase-dependent apoptosis. This identifies a functional role of the \u03b15 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 \u03b15 integrin degradation.<\/jats:p>","DOI":"10.1242\/jcs.01679","type":"journal-article","created":{"date-parts":[[2005,2,22]],"date-time":"2005-02-22T23:24:12Z","timestamp":1109114652000},"page":"1223-1232","source":"Crossref","is-referenced-by-count":83,"title":["Cbl-mediated ubiquitination of \u03b15 integrin subunit mediates fibronectin-dependent osteoblast detachment and apoptosis induced by FGFR2 activation"],"prefix":"10.1242","volume":"118","author":[{"given":"Karim","family":"Kaabeche","sequence":"first","affiliation":[{"name":"INSERM U 606, Lariboisie\u0300re Hospital, 2 rue Ambroise Pare\u0301, 75010 Paris, Universite\u0301 Paris 7, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hind","family":"Guenou","sequence":"additional","affiliation":[{"name":"INSERM U 606, Lariboisie\u0300re Hospital, 2 rue Ambroise Pare\u0301, 75010 Paris, Universite\u0301 Paris 7, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Bouvard","sequence":"additional","affiliation":[{"name":"LEDAC, UMR CNRS\/UJF 5538, Institut Albert Bonniot, Faculte\u0301 de Me\u0301decine, 38706 La Tronche CEDEX, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nade\u0300ge","family":"Didelot","sequence":"additional","affiliation":[{"name":"INSERM U 606, Lariboisie\u0300re Hospital, 2 rue Ambroise Pare\u0301, 75010 Paris, Universite\u0301 Paris 7, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antoine","family":"Listrat","sequence":"additional","affiliation":[{"name":"INSERM U 606, Lariboisie\u0300re Hospital, 2 rue Ambroise Pare\u0301, 75010 Paris, Universite\u0301 Paris 7, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre J.","family":"Marie","sequence":"additional","affiliation":[{"name":"INSERM U 606, Lariboisie\u0300re Hospital, 2 rue Ambroise Pare\u0301, 75010 Paris, Universite\u0301 Paris 7, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042519205302700_REF1","doi-asserted-by":"crossref","unstructured":"Andoniou, C. 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