Nuclear factor kappa B-inducing kinase and I kappa B kinase-alpha signal skeletal muscle cell differentiation

Nuclear factor kappaB (NF-kappaB)-inducing kinase (NIK), I kappaB kinase (I KK)-alpha and -beta, and I kappaB alpha are common elements that signal NF- kappaB activation in response to diverse stimuli. In this study, we analyze d the role of this pathway during insulin-like growth factor II. (IGF-II)-i nduced myoblast differentiation. L6E9 myoblasts differentiated with IGF-II showed an induction of NF-kappaB DNA-binding activity that correlated in ti me with the activation of IKK alpha. IKK beta, and NIK. Moreover, the activ ation of IKK alpha, IKK beta, and NIK by IGF-II was dependent on phosphatid ylinositol 3-kinase, a key regulator of myogenesis, Adenoviral transduction with the I kappaB alpha (S32A/S36A) mutant severely impaired both IGF-II-d ependent NF-kappaB activation and myoblast differentiation, indicating that phosphorylation of I kappaB alpha at Ser-32 and Ser-36 is an essential myo genic step. Adenoviral transfer of wild-type or kinase-deficient forms of I KK alpha or IKK beta revealed that IKK alpha is required for IGF-II-depende nt myoblast differentiation, whereas IKK beta is not essential for this pro cess. Finally, overexpression of kinase-proficient wild-type NIK showed tha t the activation of MK is sufficient to generate signals that trigger myoge nin expression and multinucleated myotube formation in the absence of IGF-I I.