An inactive pool of GSK-3 at the leading edge of growth cones is implicated in Semaphorin 3A signaling.
Glycogen synthase kinase (GSK)-3 is a serine/threonine kinase that has been implicated in several aspects in embryonic development and several growth factor signaling cascades. We now report that an inactive phosphorylated pool of the enzyme colocalizes with F-actin in both neuronal and nonneuronal cells. Semaphorin 3A (Sema 3A), a molecule that inhibits axonal growth, activates GSK-3 at the leading edge of neuronal growth cones and in Sema 3A-responsive human breast cancer cells, suggesting that GSK-3 activity might play a role in coupling Sema 3A signaling to changes in cell motility. We show that three different GSK-3 antagonists (LiCl, SB-216763, and SB-415286) can inhibit the growth cone collapse response induced by Sema 3A. These studies reveal a novel compartmentalization of inactive GSK-3 in cells and demonstrate for the first time a requirement for GSK-3 activity in the Sema 3A signal transduction pathway.
Eickholt
Britta J
BJ
Molecular Neurobiology Group, Medical Research Council Centre for Developmental Biology, King's College London, London SE1 1UL, United Kingdom. Britta.J.Eickholt@kcl.ac.uk
Walsh
Frank S
FS
Doherty
Patrick
P
D000199:Actins / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D004789:Enzyme Activation / Q000187:drug effects; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006023:Glycoproteins / Q000378:metabolism* / Q000494:pharmacology; D020439:Growth Cones / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011485:Protein Binding; D040121:Semaphorin-3A; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000199:Actins; D006023:Glycoproteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D040121:Semaphorin-3A; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3