title: {beta}1 Integrin and IL-3R coordinately regulate STAT5 activation and anchorage-dependent proliferation.
abstract: We previously demonstrated that integrin-dependent adhesion activates STAT5A, a well known target of IL-3-mediated signaling. Here, we show that in endothelial cells the active beta1 integrin constitutively associates with the unphosphorylated IL-3 receptor (IL-3R) beta common subunit. This association is not sufficient for activating downstream signals. Indeed, only upon fibronectin adhesion is Janus Kinase 2 (JAK2) recruited to the beta1 integrin-IL-3R complex and triggers IL-3R beta common phosphorylation, leading to the formation of docking sites for activated STAT5A. These events are IL-3 independent but require the integrity of the IL-3R beta common. IL-3 treatment increases JAK2 activation and STAT5A and STAT5B tyrosine and serine phosphorylation and leads to cell cycle progression in adherent cells. Expression of an inactive STAT5A inhibits cell cycle progression upon IL-3 treatment, identifying integrin-dependent STAT5A activation as a priming event for IL-3-mediated S phase entry. Consistently, overexpression of a constitutive active STAT5A leads to anchorage-independent cell cycle progression. Therefore, these data provide strong evidence that integrin-dependent STAT5A activation controls IL-3-mediated proliferation.
authors.affiliation: Department of Genetics, Biology and Biochemistry, University of Torino, 10126, Torino, Italy. paola.defilippi@unito.it
authors.forename: Paola
authors.initials: P
authors.lastname: Defilippi
authors.forename: Arturo
authors.initials: A
authors.lastname: Rosso
authors.forename: Patrizia
authors.initials: P
authors.lastname: Dentelli
authors.forename: Cristina
authors.initials: C
authors.lastname: Calvi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Garbarino
authors.forename: Guido
authors.initials: G
authors.lastname: Tarone
authors.forename: Luigi
authors.initials: L
authors.lastname: Pegoraro
authors.forename: Maria Felice
authors.initials: MF
authors.lastname: Brizzi
mesh_terms: D002448:Cell Adhesion / Q000502:physiology; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D007377:Interleukin-3 / Q000378:metabolism / Q000494:pharmacology; D053614:Janus Kinase 2; D008894:Milk Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D021122:Protein Subunits / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016185:Receptors, Interleukin-3 / Q000378:metabolism*; D016196:S Phase / Q000502:physiology; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology; D025521:Tumor Suppressor Proteins
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005353:Fibronectins; D019012:Integrin beta1; D007377:Interleukin-3; D008894:Milk Proteins; D021122:Protein Subunits; D011518:Proto-Oncogene Proteins; D016185:Receptors, Interleukin-3; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494095:STAT5B protein, human; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2