Cbl-mediated Degradation of Lyn and Fyn Induced by Constitutive Fibroblast Growth Factor Receptor-2 Activation Supports Osteoblast Differentiation

Kaabeche, Karim; Lemonnier, Jérôme; Mée, Sandrine Le; Caverzasio, Joseph; Marie, Pierre J.

doi:10.1074/jbc.m402469200

Cited by 79 publications

(70 citation statements)

References 62 publications

(80 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In both mice and humans, FGFR2 levels are decreased in response to the Apert FGFR2(S252W) mutation as a result of c-CBL-mediated FGFR2 ubiquitination and degradation (Kaabeche et al 2004;Holmes et al 2009). In addition, c-CBL recruitment by Apert FGFR2(S252W) in human osteoblasts causes ubiquitination and down-regulation of the Src family members LYN and FYN (Kaabeche et al 2004) and α5β1 integrin , resulting in increased osteoblast differentiation and apoptosis, respectively. Increased c-CBL recruitment in Apert osteoblasts also leads to PI3K ubiquitination and degradation, resulting in attenuation of PI3K signaling and reduced osteoblast survival (Dufour et al 2008).…”

Section: Intracellular Pathways Involved In Craniosynostosismentioning

confidence: 99%

“…The consequence is increased expression of Runx2, which is associated with premature fusion of cranial sutures in mice and humans (Zhou et al 2000;Eswarakumar et al 2002;Tanimoto et al 2004;Baroni et al 2005;Guenou et al 2005). In both mice and humans, FGFR2 levels are decreased in response to the Apert FGFR2(S252W) mutation as a result of c-CBL-mediated FGFR2 ubiquitination and degradation (Kaabeche et al 2004;Holmes et al 2009). In addition, c-CBL recruitment by Apert FGFR2(S252W) in human osteoblasts causes ubiquitination and down-regulation of the Src family members LYN and FYN (Kaabeche et al 2004) and α5β1 integrin , resulting in increased osteoblast differentiation and apoptosis, respectively.…”

Section: Intracellular Pathways Involved In Craniosynostosismentioning

confidence: 99%

See 1 more Smart Citation

Fibroblast growth factor signaling in skeletal development and disease

2015

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Intracellular Pathways Involved In Craniosynostosismentioning

confidence: 99%

Section: Intracellular Pathways Involved In Craniosynostosismentioning

confidence: 99%

Fibroblast growth factor signaling in skeletal development and disease

2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…Plusieurs mutations de c-Cbl ont en effet été identifiées chez des patients atteints de MM [30]. La plupart des mutations détectées à ce jour sont dans les domaines Linker ou RING de Cbl, domaines qui contrôlent l'activité ligase de l'enzyme et l'ostéogenèse [18][19][20]. 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].…”

Section: Rôle Des Protéines Cbl Dans L'ostéogenèseunclassified

“…La plupart des mutations détectées à ce jour sont dans les domaines Linker ou RING de Cbl, domaines qui contrôlent l'activité ligase de l'enzyme et l'ostéogenèse [18][19][20]. 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].…”

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)

View full text Add to dashboard Cite

“…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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Cbl-mediated Degradation of Lyn and Fyn Induced by Constitutive Fibroblast Growth Factor Receptor-2 Activation Supports Osteoblast Differentiation

Cited by 79 publications

References 62 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

Contact Info

Product

Resources

About