title: Fibronectin induces macrophage migration through a SFK-FAK/CSF-1R pathway.
abstract: Integrins, following binding to proteins of the extracellular matrix (ECM) including collagen, laminin and fibronectin (FN), are able to transduce molecular signals inside the cells and to regulate several biological functions such as migration, proliferation and differentiation. Besides activation of adaptor molecules and kinases, integrins transactivate Receptor Tyrosine Kinases (RTK). In particular, adhesion to the ECM may promote RTK activation in the absence of growth factors. The Colony-Stimulating Factor-1 Receptor (CSF-1R) is a RTK that supports the survival, proliferation, and motility of monocytes/macrophages, which are essential components of innate immunity and cancer development. Macrophage interaction with FN is recognized as an important aspect of host defense and wound repair. The aim of the present study was to investigate on a possible cross-talk between FN-elicited signals and CSF-1R in macrophages. FN induced migration in BAC1.2F5 and J774 murine macrophage cell lines and in human primary macrophages. Adhesion to FN determined phosphorylation of the Focal Adhesion Kinase (FAK) and Src Family Kinases (SFK) and activation of the SFK/FAK complex, as witnessed by paxillin phosphorylation. SFK activity was necessary for FAK activation and macrophage migration. Moreover, FN-induced migration was dependent on FAK in either murine macrophage cell lines or human primary macrophages. FN also induced FAK-dependent/ligand-independent CSF-1R phosphorylation, as well as the interaction between CSF-1R and β1. CSF-1R activity was necessary for FN-induced macrophage migration. Indeed, genetic or pharmacological inhibition of CSF-1R prevented FN-induced macrophage migration. Our results identified a new SFK-FAK/CSF-1R signaling pathway that mediates FN-induced migration of macrophages.
authors: a Department of Experimental and Clinical Biomedical Sciences , Università degli Studi di Firenze and Istituto Toscano Tumori , Florence , Italy.
authors: Graziana
authors: G
authors: Digiacomo
authors: a Department of Experimental and Clinical Biomedical Sciences , Università degli Studi di Firenze and Istituto Toscano Tumori , Florence , Italy.
authors: Ignazia
authors: I
authors: Tusa
authors: a Department of Experimental and Clinical Biomedical Sciences , Università degli Studi di Firenze and Istituto Toscano Tumori , Florence , Italy.
authors: Marina
authors: M
authors: Bacci
authors: a Department of Experimental and Clinical Biomedical Sciences , Università degli Studi di Firenze and Istituto Toscano Tumori , Florence , Italy.
authors: Maria Grazia
authors: MG
authors: Cipolleschi
authors: a Department of Experimental and Clinical Biomedical Sciences , Università degli Studi di Firenze and Istituto Toscano Tumori , Florence , Italy.
authors: Persio
authors: P
authors: Dello Sbarba
authors: a Department of Experimental and Clinical Biomedical Sciences , Università degli Studi di Firenze and Istituto Toscano Tumori , Florence , Italy.
authors: Elisabetta
authors: E
authors: Rovida
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005353:Fibronectins / Q000494:pharmacology*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D010766:Phosphorylation / Q000187:drug effects; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D005353:Fibronectins; D016186:Receptor, Macrophage Colony-Stimulating Factor; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases
keywords: fibronectin; migration; monocytes/macrophages; protein kinases; receptor tyrosine kinase; signal transduction