title: A role for the cytoskeleton in prolactin-dependent mammary epithelial cell differentiation.
abstract: The function of exocrine glands depends on signals within the extracellular environment. In the mammary gland, integrin-mediated adhesion to the extracellular matrix protein laminin co-operates with soluble factors such as prolactin to regulate tissue-specific gene expression. The mechanism of matrix and prolactin crosstalk and the activation of downstream signals are not fully understood. Because integrins organize the cytoskeleton, we analysed the contribution of the cytoskeleton to prolactin receptor activation and the resultant stimulation of milk protein gene expression. We show that the proximal signalling events initiated by prolactin (i.e. tyrosine phosphorylation of receptor and the associated kinase Jak2) do not depend on an intact actin cytoskeleton. However, actin networks and microtubules are both necessary for continued mammary cell differentiation, because cytoskeletal integrity is required to transduce the signals between prolactin receptor and Stat5, a transcription factor necessary for milk protein gene transcription. The two different cytoskeletal scaffolds regulate prolactin signalling through separate mechanisms that are specific to cellular differentiation but do not affect the general profile of protein synthesis.
authors.affiliation: School of Biological Sciences, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: Ghada S
authors.initials: GS
authors.lastname: Zoubiane
authors.forename: Anthony
authors.initials: A
authors.lastname: Valentijn
authors.forename: Emma T
authors.initials: ET
authors.lastname: Lowe
authors.forename: Nasreen
authors.initials: N
authors.lastname: Akhtar
authors.forename: Steve
authors.initials: S
authors.lastname: Bagley
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Gilmore
authors.forename: Charles H
authors.initials: CH
authors.lastname: Streuli
mesh_terms: D000818:Animals; D002364:Caseins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D003078:Colchicine / Q000494:pharmacology; D015638:Cytochalasin D / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D016023:Integrins / Q000378:metabolism; D053614:Janus Kinase 2; D008321:Mammary Glands, Animal / Q000378:metabolism; D051379:Mice; D008894:Milk Proteins / Q000378:metabolism; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010766:Phosphorylation; D011247:Pregnancy; D011388:Prolactin / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D011981:Receptors, Prolactin / Q000378:metabolism*; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic; D014443:Tyrosine / Q000378:metabolism
chemical_list: D002364:Caseins; D004268:DNA-Binding Proteins; D016023:Integrins; D008894:Milk Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D011518:Proto-Oncogene Proteins; D011981:Receptors, Prolactin; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D015638:Cytochalasin D; D014443:Tyrosine; D011388:Prolactin; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D003078:Colchicine