4.5 Article

Cbl-mediated ubiquitination of α5 integrin subunit mediates fibronectin-dependent osteoblast detachment and apoptosis induced by FGFR2 activation

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JOURNAL OF CELL SCIENCE
卷 118, 期 6, 页码 1223-1232

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COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.01679

关键词

osteoblast; alpha 5 integrin; FGFR2; Cbl; apoptosis; ubiquitination

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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 osteohlasts. 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 a5 integrin proteasome degradation induced by FGFR2 activation. Reduced alpha 5 integrin expression was associated with an increased Bax/Bel-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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