Involvement of SHC, GRB2, SOS and RAS in prolactin signal transduction in mammary epithelial cells.
The peptide hormone prolactin (Prl) regulates proliferation of normal and malignant mammary cells. In the present study we demonstrate that two Prl responsive cell lines, NOG-8 and T47D, activate the JAK2-SHC-MAPK pathway in a rapid and transient manner. Within 1 min of Prl treatment there was an increase in association of JAK2 with SHC, followed by rapid phosphorylation of both the 52 kDa and 46 kDa SHC proteins. Grb2 and Sos associated with the SHC proteins within 1-3 min of Prl treatment in these mammary cells. Within 5 min of hormone treatment we observe an increase in ras-GTP suggesting activation of ras. We also showed a rapid and transient tyrosine phosphorylation of STAT5 in proliferating T47D cells which reached its peak after 30 min of Prl treatment. These results indicate that Prl receptors, after binding the ligand, activate several pathways for signal transduction leading to mitogenesis.
Das
R
R
Laboratory of Tumor Immunology and Biology, National Cancer Institute, NIH, Bethesda, MD 10892-1402, USA.
Vonderhaar
B K
BK
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000503:physiopathology; D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D004848:Epithelium / Q000187:drug effects / Q000502:physiology; D051380:GRB2 Adaptor Protein; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006801:Humans; D053614:Janus Kinase 2; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D010766:Phosphorylation; D011388:Prolactin / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D011981:Receptors, Prolactin / Q000378:metabolism / Q000502:physiology; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D020664:Son of Sevenless Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; D008565:Membrane Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011981:Receptors, Prolactin; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D020664:Son of Sevenless Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014443:Tyrosine; D011388:Prolactin; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2