alpha6 integrin transactivates insulin-like growth factor receptor-1 (IGF-1R) to regulate caspase-3-mediated lens epithelial cell differentiation initiation.
Fiche publication
Date publication
février 2014
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DE ARCANGELIS Adèle
Tous les auteurs :
Basu S, Rajakaruna S, De Arcangelis A, Zhang L, Georges-Labouesse E, Menko AS
Lien Pubmed
Résumé
The canonical mitochondrial death pathway was first discovered for its role in signaling apoptosis. It has since been found to have a requisite function in differentiation initiation in many cell types including the lens through low level activation of the caspase-3 protease. The ability of this pathway to function as a molecular switch in lens differentiation depends on the concurrent induction of survival molecules in the Bcl-2 and IAP families, induced downstream of an IGF-1R/NFkappaB coordinate survival signal, to regulate caspase-3 activity. Here we investigated whether alpha6 integrin signals upstream to this IGF-1R-mediated survival-linked differentiation signal. Our findings show that IGF-1R is recruited to and activated specifically in alpha6 integrin receptor signaling complexes in the lens equatorial region, where lens epithelial cells initiate their differentiation program. In studies with both alpha6 integrin knock-out mice lenses and primary lens cell cultures following alpha6 integrin siRNA knockdown, we show that IGF-1R activation is dependent on alpha6 integrin and that this transactivation requires Src kinase activity. In addition, without alpha6 integrin, activation and expression of NFkappaB was diminished, and expression of Bcl-2 and IAP family members were down-regulated, resulting in high levels of caspase-3 activation. As a result, a number of hallmarks of lens differentiation failed to be induced; including nuclear translocation of Prox1 in the differentiation initiation zone and apoptosis was promoted. We conclude that alpha6 integrin is an essential upstream regulator of the IGF-1R survival pathway that regulates the activity level of caspase-3 for it to signal differentiation initiation of lens epithelial cells.
Référence
J Biol Chem. 2014 Feb 14;289(7):3842-55