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Volume 17, Number 10,
Issue of May 15, 1997
pp. 3515-3524
Copyright ©1997 Society for Neuroscience
Modulation of Actin Filament Behavior by GAP-43 (Neuromodulin) Is
Dependent on the Phosphorylation Status of Serine 41, the Protein
Kinase C Site
Received Dec. 19, 1996; revised March 4, 1997; accepted March 5, 1997.
Qin He,
Erik W. Dent, and
Karina F. Meiri
Departments of Pharmacology and Anatomy and Cell Biology, SUNY
Health Science Center, Syracuse, New York 13210
Synthesis of GAP-43 (also known as neuromodulin) in neurons is
induced during axon growth, and high concentrations (estimated between
50 and 100 µM) accumulate in the growth cone. GAP-43 is tightly associated with the growth cone membrane skeleton, the structure that transduces extracellular guidance cues into alterations in morphology by spatially regulating polymerization of actin filaments, thereby causing directional changes in axon growth. GAP-43
cosediments with actin filaments, and its phosphorylation on serine 41 by PKC, too, is spatially regulated so that phosphorylated GAP-43 is
found in areas where growth cones make productive, stable contacts with
other cells. In contrast, unphosphorylated GAP-43, which binds
calmodulin, is always found in parts of the growth cone that are
retracting. Here we have used a cell-free assay to investigate how the
phosphorylation status of GAP-43 affects its interactions with actin
and show that both phosphorylated and unphosphorylated GAP-43 have
different, independent effects on actin filament structure.
Phosphorylated GAP-43 stabilizes long actin filaments
(Kd = 161 nM), and antibodies to phosphorylated GAP-43 inhibit binding of actin to phalloidin, implying
a lateral interaction with filaments. In contrast, unphosphorylated GAP-43 reduces filament length distribution (Kd = 1.2 µM) and increases the critical concentration for
polymerization. Prebinding calmodulin potentiates this effect. The
results show that spatially regulated post-translational modifications
of GAP-43 within the growth cone, which can be regulated in response to extracellular signals, have the ability to directly influence the
structure of the actin cytoskeleton.
Key words:
GAP-43;
neuromodulin;
actin filaments;
growth cones;
capping proteins;
PKC phosphorylation
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