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Volume 17, Number 24,
Issue of December 15, 1997
pp. 9466-9472
Study of Proline-Directed Protein Kinases Involved in
Phosphorylation of the Heavy Neurofilament Subunit
Received Sept. 30, 1997; accepted Oct. 1, 1997.
Benoit I. Giasson and
Walter E. Mushynski
McGill University, Department of Biochemistry, Montréal,
Québec, Canada H3G 1Y6
The high-molecular-mass neurofilament subunit (NFH) is normally
hypophosphorylated in the neuronal perikaryon and undergoes extensive
phosphorylation after entering the initial axon segment. Aberrant
hyperphosphorylation of perikaryal NFH is a common feature of many
neurological diseases. In a previous study (), we demonstrated a correlation between phosphorylation of
perikaryal NFH and induction of stress-activated protein kinase (SAPK)- . In this report, we present direct evidence showing that the
in vivo activation of SAPKs by an upstream activator
(MEKK-1) caused extensive NFH phosphorylation. We also show that
stress-activated p38 kinases were not involved in the phosphorylation
of perikaryal NFH in cultured dorsal root ganglion neurons and that
this process was reversible. SAPK was shown to be located in both
the cell body and the neurites of the cultured neurons, suggesting that it is likely to be involved in the phosphorylation of cytoplasmic substrates. These could include neuritic NFH, which is highly phosphorylated despite the demonstrated lack of cyclin-dependent kinase-5 activity in these neurons. Neuritic NFH was also highly phosphorylated in neuronal cultures devoid of Schwann cells, indicating that this form of post-translational modification does not require cues
stemming from Schwann cell-axon contacts. Collectively, these findings
provide significant new insights into mechanisms involved in NFH
phosphorylation in normal neurons and in disease states characterized
by aberrant phosphorylation of neurofilaments.
Key words:
cyclin-dependent kinase-5;
heavy neurofilament-subunit;
p38-kinases;
phosphorylation;
stress-activated kinases
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