Rac1 links integrin-mediated adhesion to the control of lactational differentiation in mammary epithelia.
The expression of tissue-specific genes during mammary gland differentiation relies on the coincidence of two distinct signaling events: the continued engagement of beta1 integrins with the extracellular matrix (ECM) and a hormonal stimulus from prolactin (Prl). How the integrin and Prl receptor (PrlR) systems integrate to regulate milk protein gene synthesis is unknown. In this study, we identify Rac1 as a key link. Dominant-negative Rac1 prevents Prl-induced synthesis of the milk protein beta-casein in primary mammary epithelial cells cultured as three-dimensional acini on basement membrane. Conversely, activated Rac1 rescues the defective beta-casein synthesis that occurs under conditions not normally permissive for mammary differentiation, either in beta1 integrin-null cells or in wild-type cells cultured on collagen. Rac1 is required downstream of integrins for activation of the PrlR/Stat5 signaling cascade. Cdc42 is also necessary for milk protein synthesis but functions via a distinct mechanism to Rac1. This study identifies the integration of signals provided by ECM and hormones as a novel role for Rho family guanosine triphosphatases.
Akhtar
Nasreen
N
Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, England, United Kingdom.
Streuli
Charles H
CH
D000818:Animals; D002364:Caseins / Q000096:biosynthesis / Q000187:drug effects; D002448:Cell Adhesion / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism / Q000502:physiology*; D005109:Extracellular Matrix / Q000502:physiology; D005260:Female; D020558:GTP Phosphohydrolases / Q000502:physiology; D020690:GTPase-Activating Proteins / Q000187:drug effects / Q000494:pharmacology / Q000502:physiology; D019012:Integrin beta1 / Q000378:metabolism*; D007774:Lactation / Q000378:metabolism*; D008321:Mammary Glands, Animal / Q000502:physiology; D051379:Mice; D008813:Mice, Inbred ICR; D009479:Neuropeptides / Q000378:metabolism* / Q000494:pharmacology; D011247:Pregnancy; D011388:Prolactin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D020744:rac GTP-Binding Proteins / Q000378:metabolism* / Q000494:pharmacology; D020830:rac1 GTP-Binding Protein
C115491:Arhgap31 protein, mouse; D002364:Caseins; D020690:GTPase-Activating Proteins; D019012:Integrin beta1; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D011388:Prolactin; D020558:GTP Phosphohydrolases; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein