Regulation of mammary differentiation by extracellular matrix involves protein-tyrosine phosphatases.
Extracellular matrix and growth factors cooperate to regulate signaling pathways and gene transcription in adherent cells. However, the mechanism of extracellular matrix signaling is poorly defined. In mammary gland, the expression of milk protein genes is controlled by cross-talk between signals derived from the basement membrane protein, laminin, and the lactogenic hormone, prolactin. Signals from basement membrane are transduced by beta1 integrins and are required for prolactin to activate DNA binding of the milk protein gene transcription factor, Stat5. Here we show that basement membrane is necessary for tyrosine phosphorylation of the prolactin receptor and thus directly affects cytokine signaling and differentiation at the level of the plasma membrane. Prolactin does not induce tyrosine phosphorylation of its receptor, Jak2, or Stat5 in nondifferentiated breast epithelia cultured on collagen I, and we show that this is due to a vanadate-sensitive activity that inhibits the prolactin pathway. We suggest that protein-tyrosine phosphatases are novel targets for regulation by extracellular matrix and in mammary cells represent an additional control to the requirement of integrins for milk protein production.
Edwards
G M
GM
School of Biological Sciences, University of Manchester, 3.239 Stopford Building, Oxford Road, Manchester, M13 9PT, United Kingdom.
Wilford
F H
FH
Liu
X
X
Hennighausen
L
L
Djiane
J
J
Streuli
C H
CH
D000818:Animals; D001485:Basement Membrane / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D005109:Extracellular Matrix / Q000502:physiology*; D005260:Female; D019012:Integrin beta1 / Q000502:physiology; D053614:Janus Kinase 2; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008813:Mice, Inbred ICR; D008894:Milk Proteins; D019000:Phosphotyrosine / Q000378:metabolism; D011247:Pregnancy; D011388:Prolactin / Q000502:physiology*; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D011981:Receptors, Prolactin / Q000502:physiology; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism; D014638:Vanadates / Q000494:pharmacology
D004268:DNA-Binding Proteins; D019012:Integrin beta1; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D011981:Receptors, Prolactin; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; C076715:pervanadate; D019000:Phosphotyrosine; D014638:Vanadates; D011388:Prolactin; D003094:Collagen; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D017027:Protein Tyrosine Phosphatases