Calcium influx induces neurite growth through a Src-Ras signaling cassette.
We find that calcium influx through voltage-dependent calcium channels causes extensive neurite outgrowth in PC12 cells. The calcium signal transduction pathway promoting neurite outgrowth causes the rapid activation of protein tyrosine kinases, which include Src. Protein tyrosine phosphorylation results in the formation of an Shc/Grb2 complex, leading to Ras activation, MAP kinase activation, and the subsequent induction of the immediate early gene NGFI-A. Protein tyrosine phosphorylation, gene induction, and neurite outgrowth are inhibited by the expression of dominant negative forms of both Src and Ras, indicating a requirement for both proto-oncoproteins in calcium signaling. Our results suggest that a signaling cassette which includes Src and Ras is likely to underlie a broad range of calcium of actions in the nervous system.
Rusanescu
G
G
Department of Neurobiology and Behavior, State University of New York at Stony Brook 11794-5230, USA.
Qi
H
H
Thomas
S M
SM
Brugge
J S
JS
Halegoua
S
S
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002462:Cell Membrane / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics; D051766:Early Growth Response Protein 1; D004594:Electrophysiology; D051380:GRB2 Adaptor Protein; D005786:Gene Expression Regulation; D011905:Genes, ras; D016391:Genes, src; D017874:Immediate-Early Proteins; D016501:Neurites / Q000502:physiology*; D016716:PC12 Cells; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics; D015533:Transcriptional Activation; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D051380:GRB2 Adaptor Protein; C495950:Grb2 protein, rat; D017874:Immediate-Early Proteins; D011506:Proteins; D014157:Transcription Factors; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium