FGFR2-Cbl interaction in lipid rafts triggers attenuation of PI3K/Akt signaling and osteoblast survival

Dufour, Cécilie; Guénou, Hind; Kaabeche, Karim; Bouvard, Daniel; Sanjay, Archana; Marie, Pierre J.

doi:10.1016/j.bone.2008.02.009

Cited by 48 publications

(46 citation statements)

References 47 publications

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“…The E3 ubiquitin ligase CBL inhibits FGFR signaling by forming a ternary complex with phospho-FRS2 and GRB2, where it promotes the ubiquitination and degradation of the FGFR and FRS2 (Wong et al 2002). CBL also interacts with PI3K, leading to its ubiquitination and degradation (Dufour et al 2008). The adaptor protein Grb14 binds to FGFR phospho-Tyr766 and interferes with phosphorylation and activation of PLCγ (Browaeys-Poly et al 2010).…”

Section: Fgf Signalingmentioning

confidence: 99%

“…In osteoblasts, CBL plays an important role in down-regulation of activated FGFR signaling and subsequently in the control of osteoblastogenesis (Severe et al 2013). FGFR2 ubiquitination by c-CBL leads to FGFR2 down-regulation and subsequent reduction in osteogenic differentiation capacity, whereas inhibition of c-CBL interaction with FGFR2 promotes osteoblast differentiation and osteogenic differentiation through increased ERK1/2 and PI3K signaling (Dufour et al 2008). This highlights the essential role of c-CBL-mediated regulation of FGFR signaling in osteoblastogenesis (Severe et al 2013).…”

Section: Intramembranous Mesenchymal Condensationsmentioning

confidence: 99%

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Fibroblast growth factor signaling in skeletal development and disease

2015

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Fibroblast growth factor (FGF) signaling pathways are essential regulators of vertebrate skeletal development. FGF signaling regulates development of the limb bud and formation of the mesenchymal condensation and has key roles in regulating chondrogenesis, osteogenesis, and bone and mineral homeostasis. This review updates our review on FGFs in skeletal development published in Genes & Development in 2002, examines progress made on understanding the functions of the FGF signaling pathway during critical stages of skeletogenesis, and explores the mechanisms by which mutations in FGF signaling molecules cause skeletal malformations in humans. Links between FGF signaling pathways and other interacting pathways that are critical for skeletal development and could be exploited to treat genetic diseases and repair bone are also explored.

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Section: Fgf Signalingmentioning

confidence: 99%

Section: Intramembranous Mesenchymal Condensationsmentioning

confidence: 99%

Fibroblast growth factor signaling in skeletal development and disease

2015

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“…Inversement, l'expression d'un c-Cbl muté dans le domaine RING (7OZ-Cbl) restaure l'expression de Lyn et Fyn et diminue l'expression des gènes ostéoblastiques [18]. Enfin, le recrutement de c-Cbl par le FGFR2 activé atténue l'activité de la voie PI3K/Akt, ce qui favorise la mort cellulaire des ostéoblastes [21]. L'activation de c-Cbl induit aussi une diminution de l'expression de l'intégrine 5, ce qui augmente l'apoptose des ostéoblastes [21,22].…”

Section: Rôle Des Protéines Cbl Dans L'ostéogenèseunclassified

“…Enfin, le recrutement de c-Cbl par le FGFR2 activé atténue l'activité de la voie PI3K/Akt, ce qui favorise la mort cellulaire des ostéoblastes [21]. L'activation de c-Cbl induit aussi une diminution de l'expression de l'intégrine 5, ce qui augmente l'apoptose des ostéoblastes [21,22]. À l'inverse, l'inhibition de l'interaction entre c-Cbl et la PI3K par l'expression d'un Cbl muté (Y 737 FCbl) favorise la prolifération des ostéoblastes et augmente la formation osseuse chez la souris [23].…”

Section: Rôle Des Protéines Cbl Dans L'ostéogenèseunclassified

Rôle de l’ubiquitine ligase c-Cbl dans l’ostéogenèse normale et cancéreuse

Sévère¹,

Marie²

2012

Med Sci (Paris)

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“…The c-Cbl function is mediated by the RING finger domain which allows the recruitment of ubiquitin-conjugated enzymes (E2) and is responsible for ubiquitin ligase activity and by the N-terminal domain which interacts with the phosphotyrosine residues of multiple protein tyrosine kinases, resulting in ubiquitination and proteasome degradation of targeted proteins [31,32]. We and others have previously shown that this E3 ubiquitin ligase controls the ubiquitination and proteasome degradation of several important signaling proteins in osteoblasts [33][34][35][36][37][38]. However, the role of c-Cbl in the control of mesenchymal osteoblast progenitor cell differentiation remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Promotion of Osteoblast Differentiation in Mesenchymal Cells Through Cbl-Mediated Control of STAT5 Activity

et al. 2013

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The identification of the molecular mechanisms controlling the degradation of regulatory proteins in mesenchymal stromal cells (MSC) may provide clues to promote MSC osteogenic differentiation and bone regeneration. Ubiquitin ligase-dependent degradation of proteins is an important process governing cell fate. In this study, we investigated the role of the E3 ubiquitin ligase c-Cbl in MSC osteoblast differentiation and identified the mechanisms involved in this effect. Using distinct shRNA targeting c-Cbl, we showed that c-Cbl silencing promotes osteoblast differentiation in murine and human MSC, as demonstrated by increased alkaline phosphatase activity, expression of phenotypic osteoblast marker genes (RUNX2, ALP, type 1 collagen), and matrix mineralization in vitro. Coimmunoprecipitation analyses showed that c-Cbl interacts with the transcription factor STAT5, and that STAT5 forms a complex with RUNX2, a master transcription factor controlling osteoblastogenesis. Silencing c-Cbl decreased c-Cblmediated STAT5 ubiquitination, increased STAT5 protein level and phosphorylation, and enhanced STAT5 and RUNX2 transcriptional activity. The expression of insulin like growth factor-1 (IGF-1), a target gene of STAT5, was increased by c-Cbl silencing in MSC and in bone marrow stromal cells isolated from c-Cbl deficient mice, suggesting that IGF-1 contributes to osteoblast differentiation induced by c-Cbl silencing in MSC. Consistent with these findings, pharmacological inhibition of STAT5 activity, or neutralization of IGF-1 activity, abrogated the positive effect of c-Cbl knockdown on MSC osteogenic differentiation. Taken together, the data provide a novel functional mechanism by which the ubiquitin ligase c-Cbl regulates the osteoblastic differentiation program in mesenchymal cells by controlling Cbl-mediated STAT5 degradation and activity.

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FGFR2-Cbl interaction in lipid rafts triggers attenuation of PI3K/Akt signaling and osteoblast survival

Cited by 48 publications

References 47 publications

Fibroblast growth factor signaling in skeletal development and disease

Fibroblast growth factor signaling in skeletal development and disease

Rôle de l’ubiquitine ligase c-Cbl dans l’ostéogenèse normale et cancéreuse

Promotion of Osteoblast Differentiation in Mesenchymal Cells Through Cbl-Mediated Control of STAT5 Activity

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