Estradiol (E2) elicits SRC phosphorylation in the mouse neocortex: the initial event in E2 activation of the MAPK cascade?
In neocortical explants, E2 activates various signaling components of the MAPK cascade, including B-Raf and MAPK kinase-dependent ERK, suggesting a possible role in the differentiative actions of E2 in the brain. To further characterize the signaling pathways activated by E2, we determined whether c-Src, a member of the Src family of nonreceptor tyrosine kinases and an important modulator of both the MAPK cascade and neuronal differentiation, may play a role in E2 signaling. The present studies show for the first time in the brain that E2 elicits phosphorylation of c-Src on three functionally critical tyrosine residues (Y220, Y423, and Y534), and that this phosphorylation occurs despite disruption of ER alpha (in ER knockout mice). PP2, a Src family kinase inhibitor, suppressed not only E2-induced phosphorylation of c-Src, but ERK phosphorylation as well, suggesting that c-Src may be an upstream regulator of E2 signaling. E2-induced phosphorylation of c-Src is associated with increased tyrosine phosphorylation of Shc, increased association of Shc with Grb2, and induction of Ras, but not Rap1, activation. Together, these data provide evidence that E2 activates a novel c-Src-dependent signal transduction pathway in the developing brain.
Nethrapalli
I S
IS
Department of Anatomy and Cell Biology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Singh
M
M
Guan
X
X
Guo
Q
Q
Lubahn
D B
DB
Korach
K S
KS
Toran-Allerand
C D
CD
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D004268:DNA-Binding Proteins / Q000494:pharmacology; D004789:Enzyme Activation; D004958:Estradiol / Q000494:pharmacology*; D051380:GRB2 Adaptor Protein; D016391:Genes, src; D019751:Intramolecular Transferases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019579:Neocortex / Q000378:metabolism*; D009924:Organ Culture Techniques; D010766:Phosphorylation / Q000187:drug effects; D010940:Plant Proteins / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D012016:Reference Values; D020827:rap1 GTP-Binding Proteins / Q000502:physiology; D018631:ras Proteins / Q000502:physiology; D019061:src-Family Kinases
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; D010940:Plant Proteins; D011506:Proteins; C083694:phloem protein-2, Physcomitrella patens; D004958:Estradiol; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; D020928:Mitogen-Activated Protein Kinases; D020827:rap1 GTP-Binding Proteins; D018631:ras Proteins; D019751:Intramolecular Transferases; C066630:squalene-hopene cyclase