Nuclear factor-κB activation via tyrosine phosphorylation of inhibitor κB-α is crucial for ciliary neurotrophic factor-promoted neurite growth from developing neurons

The cytokine ciliary neurotrophic factor (CNTF) promotes the growth of neural processes from many kinds of neurons in the developing and regenerating adult nervous system, but the intracellular signaling mechanisms mediating this important function of CNTF are poorly understood. Here, we show that CNTF activates the nuclear factor-κB (NF-κB) transcriptional system in neonatal sensory neurons and that blocking NF-κB-dependent transcription inhibits CNTF-promoted neurite growth. Selectively blocking NF-κB activation by the noncanonical pathway that requires tyrosine phosphorylation of inhibitor κB-α(IκB-α), but not by the canonical pathway that requires serine phosphorylation of IκB-α, also effectively inhibits CNTF-promoted neurite growth. CNTF treatment activates spleen tyrosine kinase (SYK) whose substrates include IκB-α. CNTF-induced SYK phosphorylation is rapidly followed by increased tyrosine phosphorylation of IκB-α, and blocking SYK activation or tyrosine phosphorylation of IκB-α prevents CNTF-induced NF-κB activation and CNTF-promoted neurite growth. These findings demonstrate that NF-κB signaling by an unusual activation mechanism is essential for the ability of CNTF to promote the growth of neural processes in the developing nervous system.