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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.
Abbreviations
| CSF-1 | = | Colony-Stimulating Factor-1 |
| CSF-1R | = | CSF-1 Receptor |
| RTK | = | Receptor Tyrosine Kinase |
| FN | = | fibronectin |
| PL | = | polylysine |
| FBS | = | foetal bovine serum |
| DMEM | = | Dulbecco's modified eagle medium |
| RPMI | = | Roswell Park Memorial Institute |
| ERK | = | Extracellular signal-Regulated Kinase |
| M-CSF | = | Macrophage Colony-Stimulating Factor |
| GAPDH | = | glyceraldehyde-3-phosphate dehydrogenase |
| SFK | = | Src Family Kinases |
| MEK | = | Mitogen-activated ERK Kinase |
| siRNA | = | small interfering RNA |
| DMSO | = | dimethylsulfoxide |
| CD | = | cytochalasin D |
| FAK | = | Focal Adhesion Kinase |
| SEM | = | standard error of the mean |
Disclosure of potential conflicts of interest
No potential conflicts of interest were disclosed.
Author contributions
GD, MGC, ER, MB and IT performed experiments. ER and GD designed experiments. GD and ER analyzed results and wrote the paper together with PDS.
Funding
This work was supported by grants from Associazione Italiana per la Ricerca sul Cancro (AIRC, #IG13466 to PDS, #IG15282 to ER), Istituto Toscano Tumori (PDS), Ministero della Salute (Ricerca Finalizzata, Grant #RF-TOS-2008-1163728 to PDS), Regione Toscana (Programma per la Ricerca in Materia di Salute to PDS), Fondazione Cassa di Risparmio di Volterra (PDS) and Università degli Studi di Firenze (Fondo di Ateneo ex-60 %; ER).