Semaphorin 3F antagonizes neurotrophin-induced phosphatidylinositol 3-kinase and mitogen-activated protein kinase kinase signaling: a mechanism for growth cone collapse.
Peripheral nerve growth is regulated by the coordinated action of numerous external stimuli, including positively acting neurotrophin-derived growth cues and restrictive semaphorin cues. Here, we show that Semaphorin 3F (Sema 3F) can antagonize nerve growth factor (NGF)-stimulated TrkA (tyrosine receptor kinase A) signaling in sympathetic neurons, thereby apparently contributing to growth cone collapse. Sema 3F suppressed NGF-induced activation of the phosphatidylinositol 3 (PI3)-kinase-Akt and MEK (mitogen-activated protein kinase kinase)-ERK (extracellular signal-regulated kinase) pathways, both of which we show to be required to maintain growth cone structure. Sema 3F-induced growth cone collapse was partially reversed by sustained activation of the PI3-kinase and MEK pathways, which was achieved by overexpression of the Gab-1 (growth-associated binder 1) docking protein. These data indicate that a novel mechanism used by Sema 3F to collapse growth cones in sympathetic neurons is to dampen neurotrophin signaling, providing an intracellular mechanism for cross talk between positive and negative axon growth cues.
Atwal
Jasvinder K
JK
The Hospital for Sick Children, Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada M5G 1X8.
Singh
Karun K
KK
Tessier-Lavigne
Marc
M
Miller
Freda D
FD
Kaplan
David R
DR
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000648:ultrastructure; D019556:COS Cells; D002478:Cells, Cultured; D020439:Growth Cones / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008565:Membrane Proteins / Q000494:pharmacology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020932:Nerve Growth Factor / Q000037:antagonists & inhibitors*; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D020917:Receptor, trkA / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D013564:Sympathetic Nervous System / Q000166:cytology
D048868:Adaptor Proteins, Signal Transducing; C490897:Gab1 protein, mouse; C490896:Gab1 protein, rat; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; C491230:SEMA3F protein, human; C491229:Sema3f protein, mouse; D020932:Nerve Growth Factor; D020917:Receptor, trkA; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases