DDR1 signaling is essential to sustain Stat5 function during lactogenesis.
Postnatal development of the mammary gland is achieved by an interplay of endocrine and extracellular matrix-derived signals. Despite intense research, a comprehensive understanding of the temporal and spatial coordination of these hormonal and basement membrane stimuli is still lacking. Here, we address the role of the collagen-receptor DDR1 in integrating extracellular matrix-derived signaling with the lactogenic pathway initiated by the prolactin receptor. We found that stimulation of DDR1-overexpressing mammary epithelial HC11 cells with collagen and prolactin resulted in stronger and more sustained induction of Stat5 phosphorylation as compared to control cells. Enhanced Stat5 activity in HC11-DDR1 cells correlated with increased beta-casein gene expression. In contrast, cells derived from DDR1-null mice showed reduced Stat5 activation upon lactogenic stimulation and completely failed to induce beta-casein expression. The cell-autonomous role of DDR1 in controlling ductal branching and alveologenesis prior to the onset of lactogenesis was corroborated by mammary tissue transplantation experiments. Our results show that aside from hormone- and cytokine receptors, DDR1 signaling establishes a third matrix-derived pathway vital to maintain mammary gland function.
Faraci-Orf
Elena
E
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
McFadden
Catherine
C
Vogel
Wolfgang F
WF
D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D017931:DNA Primers; D000070819:Discoidin Domain Receptor 1; D024202:Electrophoretic Mobility Shift Assay; D047468:Immunoprecipitation; D007774:Lactation; D008321:Mammary Glands, Animal / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000502:physiology*
D017931:DNA Primers; D008565:Membrane Proteins; D050799:STAT5 Transcription Factor; C083249:Ddr1 protein, mouse; D000070819:Discoidin Domain Receptor 1; D020794:Receptor Protein-Tyrosine Kinases