Nuclear factor kappa B-inducing kinase and Ikappa B kinase-alpha signal skeletal muscle cell differentiation.
Nuclear factor kappaB (NF-kappaB)-inducing kinase (NIK), IkappaB kinase (IKK)-alpha and -beta, and IkappaBalpha are common elements that signal NF-kappaB activation in response to diverse stimuli. In this study, we analyzed the role of this pathway during insulin-like growth factor II (IGF-II)-induced myoblast differentiation. L6E9 myoblasts differentiated with IGF-II showed an induction of NF-kappaB DNA-binding activity that correlated in time with the activation of IKKalpha, IKKbeta, and NIK. Moreover, the activation of IKKalpha, IKKbeta, and NIK by IGF-II was dependent on phosphatidylinositol 3-kinase, a key regulator of myogenesis. Adenoviral transduction with the IkappaBalpha(S32A/S36A) mutant severely impaired both IGF-II-dependent NF-kappaB activation and myoblast differentiation, indicating that phosphorylation of IkappaBalpha at Ser-32 and Ser-36 is an essential myogenic step. Adenoviral transfer of wild-type or kinase-deficient forms of IKKalpha or IKKbeta revealed that IKKalpha is required for IGF-II-dependent myoblast differentiation, whereas IKKbeta is not essential for this process. Finally, overexpression of kinase-proficient wild-type NIK showed that the activation of NIK is sufficient to generate signals that trigger myogenin expression and multinucleated myotube formation in the absence of IGF-II.
Departament de Bioquimica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, E-08028 Barcelona, Spain.
J
J
Canicio
P
P
Ruiz-Lozano
M
M
Carrasco
M
M
Palacin
K
K
Chien
A
A
Zorzano
P
P
Kaliman
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004790:Enzyme Induction; D051550:I-kappa B Kinase; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology; D018482:Muscle, Skeletal / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000378:metabolism*; D051381:Rats; D000097782:NF-kappaB-Inducing Kinase
D051550:I-kappa B Kinase; D007335:Insulin-Like Growth Factor II; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase