c-Src-null mice exhibit defects in normal mammary gland development and ERalpha signaling.
The c-Src tyrosine kinase has been implicated to play an integral role in modulating growth factor receptor, integrin and steroid receptor function. One class of steroid receptors that c-Src modulates is the estrogen receptor alpha (ERalpha). Although there is strong biochemical evidence supporting a role for c-Src in ERalpha signaling, the consequence of this association is unclear at the biological level. To explore the significance of c-Src in ERalpha signaling, we studied the development of various reproductive organs that are dependent on ERalpha in c-Src-deficient mice. We show that the loss of the c-Src tyrosine kinase correlates with defects in ductal development as well as in uterine and ovarian development. Genetic and biochemical analyses of c-Src-deficient mammary epithelial cells also revealed defects in the ability of mammary epithelial cells to activate a number of signaling pathways in response to exogenous estrogen stimulation. Taken together, these studies demonstrate that c-Src plays a role in ERalpha signaling in vivo.
Kim
Harold
H
Department of Medical Sciences, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4K1.
Laing
Mike
M
Muller
William
W
D000818:Animals; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008321:Mammary Glands, Animal / Q000002:abnormalities / Q000254:growth & development* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010053:Ovary / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction; D014599:Uterus / Q000378:metabolism; D019061:src-Family Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*
D047628:Estrogen Receptor alpha; D004967:Estrogens; D011518:Proto-Oncogene Proteins; D011960:Receptors, Estrogen; D019938:Cyclin D1; D019061:src-Family Kinases; D000071679:Glycogen Synthase Kinase 3 beta; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3