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J. Biol. Chem., Vol. 278, Issue 26, 24026-24032, June 27, 2003

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Phosphorylation of the Head Domain of Neurofilament Protein (NF-M)

A FACTOR REGULATING TOPOGRAPHIC PHOSPHORYLATION OF NF-M TAIL DOMAIN KSP SITES IN NEURONS^*

Ya-li Zheng, Bing-Sheng Li, Veeranna  and Harish C. Pant 

From the Laboratory of Neurochemistry, NINDS, National Institutes of Health, Bethesda, Maryland 20892

In neurons the phosphorylation of neurofilament (NF) proteins NF-M and NF-H is topographically regulated. Although kinases and NF subunits are synthesized in cell bodies, extensive phosphorylation of the KSP repeats in tail domains of NF-M and NF-H occurs primarily in axons. The nature of this regulation, however, is not understood. As obligate heteropolymers, NF assembly requires interactions between the core NF-L with NF-M or NF-H subunits, a process inhibited by NF head domain phosphorylation. Phosphorylation of head domains at protein kinase A (PKA)-specific sites seems to occur transiently in cell bodies after NF subunit synthesis. We have proposed that transient phosphorylation of head domains prevents NF assembly in the soma and inhibits tail domain phosphorylation; i.e. assembly and KSP phosphorylation in axons depends on prior dephosphorylation of head domain sites. Deregulation of this process leads to pathological accumulations of phosphorylated NFs in the soma as seen in some neurodegenerative disorders. To test this hypothesis, we studied the effect of PKA phosphorylation of the NF-M head domain on phosphorylation of tail domain KSP sites. In rat cortical neurons we showed that head domain phosphorylation of endogenous NF-M by forskolin-activated PKA inhibits NF-M tail domain phosphorylation. To demonstrate the site specificity of PKA phosphorylation and its effect on tail domain phosphorylation, we transfected NIH3T3 cells with NF-M mutated at PKA-specific head domain serine residues. Epidermal growth factor stimulation of cells with mutant NF-M in the presence of forskolin exhibited no inhibition of NF-tail domain phosphorylation compared with the wild type NF-M-transfected cells. This is consistent with our hypothesis that transient phosphorylation of NF-M head domains inhibits tail domain phosphorylation and suggests this as one of several mechanisms underlying topographic regulation.

Received for publication, March 25, 2003

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Current address: Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962.

To whom correspondence should be addressed: Laboratory of Neurochemistry, NINDS, National Institutes of Health, Bldg. 36, Rm. 4D04, 9000 Rockville Pike, Bethesda, MD 20892-4130. Tel.: 301-402-2124; Fax: 301-496-1339; E-mail: panth{at}ninds.nih.gov.

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