Activation of raf-1, MEK, and MAP kinase in prolactin responsive mammary cells.
The polypeptide hormone prolactin (Prl), acting through its cell surface receptors, promotes growth and differentiation in normal and malignant breast cells. We demonstrate herein that two Prl-responsive cell lines, NOG-8 normal mouse mammary epithelial and T47D human breast cancer cells, respond to Prl by rapid and transient activation of a series of kinases. Raf-1 was activated within 2-5 min of Prl treatment. This was followed rapidly by activation of MEK (MAP kinase kinase) and MAP kinase activity in these cells. Increased MAP kinase activity was accompanied by tyrosine phosphorylation of both the 42 kDa and 44 kDa isoforms. The tyrosine kinase inhibitors genestein and tyrphostin blocked the increase in MAP kinase activity as well as Prl induced growth of the T47D cells. These results indicate that the Prl receptor, after binding to Prl in mammary cells, activates the raf-MEK-MAP kinase pathway for signal transduction leading to mitogenesis.
Das
R
R
Laboratory of Tumor Immunology and Biology, National Cancer Institute, Bethesda, MD 20892-1402, USA.
Vonderhaar
B K
BK
D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D019833:Genistein; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology; D048728:MAP Kinase Kinase Kinase 1; D008321:Mammary Glands, Animal / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D011388:Prolactin / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf
D004791:Enzyme Inhibitors; D007529:Isoflavones; D011518:Proto-Oncogene Proteins; D011388:Prolactin; D019833:Genistein; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; C482578:Map3k1 protein, mouse