Abstract
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.
Highlights
The IGFs1 are the only known growth factors that are crucial to myogenesis [1]
To analyze the mechanism required by insulin-like growth factor II (IGF-II) for Nuclear factor B (NF-B) activation during differentiation, L6E9 myoblasts were transduced with an adenovirus expressing an IB␣ mutant with Ser-32 and Ser-36 replaced by alanine residues (adv/IB␣(S32A/S36A))
L6E9 myoblasts differentiated for 24 h with IGF-II exhibited an induction of NF-B DNA-binding activity (Fig. 1A), which was blocked in myoblasts overexpressing IB␣(S32A/S36A) (Fig. 1B)
Summary
The IGFs1 are the only known growth factors that are crucial to myogenesis [1]. IGF-I and IGF-II switch on the myogenic program through the IGF-I receptor [2], activating the expression of myogenic transcription factors, cell cycle arrest, musclespecific protein expression, and cell fusion to form multinucleated myotubes [3, 4]. These data suggest that IGF-II requires NF-B activation through a mechanism that involves IB␣ phosphorylation to trigger skeletal muscle cell differentiation.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
