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 α5 integrin subunit normally expressed in human calvarial osteoblasts in vivo. Treatment with lactacystin, a potent inhibitor of proteasome, restored α5 integrin levels in FGFR2 mutant osteoblasts. Immunoprecipitation analysis showed that α5 integrin interacts with both the E3 ubiquitin ligase Cbl and ubiquitin. Immunocytochemistry revealed that α5 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 α5 integrin levels. This suggests that Cbl-mediated ubiquitination plays an essential role in α5 integrin proteasome degradation induced by FGFR2 activation. Reduced α5 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 α5 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 α5 integrin degradation by the proteasome, which results in reduced osteoblast attachment on fibronectin and caspase-dependent apoptosis. This identifies a functional role of the α5 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 α5 integrin degradation.

Large series of cauda equina tumors in adults are seldom reported. This French series retrospectively reviews 231 cases collected for the congress of the Societe Francaise de Neurochirurgie in 1996. The authors first analyze this series and then discuss the pertinent literature. Schwannoma was the most frequent benign tumor in this series, followed by ependymoma. Very few malignant tumors were recorded; these were usually malignant neurinomas nearly always in neurofibromatosis patients. Some other rare tumors were also recorded, including paragangliomas. This series confirms the importance of the pretherapeutic neurological status in functional prognosis. All schwannomas can be cured, while ependymomas and paragangliomas may recur after a very long delay. Surgery must be as complete as possible, since adjuvant therapies are proven to have little efficacy. This type of tumor requires very long follow-up. Prognosis is good for hemangioblastomas. Sphincter dysfunctions carries a poor prognosis and may appear after primary surgery, more often after treatment of recurrences.

Papillary tumors of the pineal region constitute a rare entity, with a difficult diagnosis, an uncertain prognosis, and a high risk of local recurrence; they must be treated by a combination of surgery and radiotherapy. The only identified prognostic factor is the complete or incomplete nature of surgical resection.