Nuclear factor-kappaB activation via tyrosine phosphorylation of inhibitor kappaB-alpha 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-kappaB (NF-kappaB) transcriptional system in neonatal sensory neurons and that blocking NF-kappaB-dependent transcription inhibits CNTF-promoted neurite growth. Selectively blocking NF-kappaB activation by the noncanonical pathway that requires tyrosine phosphorylation of inhibitor kappaB-alpha (IkappaB-alpha), but not by the canonical pathway that requires serine phosphorylation of IkappaB-alpha, also effectively inhibits CNTF-promoted neurite growth. CNTF treatment activates spleen tyrosine kinase (SYK) whose substrates include IkappaB-alpha. CNTF-induced SYK phosphorylation is rapidly followed by increased tyrosine phosphorylation of IkappaB-alpha, and blocking SYK activation or tyrosine phosphorylation of IkappaB-alpha prevents CNTF-induced NF-kappaB activation and CNTF-promoted neurite growth. These findings demonstrate that NF-kappaB 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.