title: EphrinA1 repulsive response is regulated by an EphA2 tyrosine phosphatase.
abstract: Ephrin kinases and their ephrin ligands transduce repulsion of cells in axon guidance, migration, invasiveness, and tumor growth, exerting a negative signaling on cell proliferation and adhesion. A key role of their kinase activity has been confirmed by mutant kinase inactive receptors that shift the cellular response from repulsion to adhesion. Our present study aimed to investigate the role of low molecular weight protein-tyrosine phosphatase (LMW-PTP) in ephrinA1/EphA2 signaling. LMW-PTP, by means of dephosphorylation of EphA2 kinase, negatively regulates the ephrinA1-mediated repulsive response, cell proliferation, cell adhesion and spreading, and the formation of retraction fibers, thereby confirming the relevance of the net level of tyrosine phosphorylation of Eph receptors. LMW-PTP interferes with ephrin-mediated mitogen-activated protein kinase signaling likely through inhibition of p120RasGAP binding to the activated EphA2 kinase, thereby confirming the key role of mitogen-activated protein kinase inhibition by ephrinA1 repulsive signaling. We conclude that LMW-PTP acts as a terminator of EphA2 signaling causing an efficient negative feedback loop on the biological response mediated by ephrinA1 and pointing on tyrosine phosphorylation as the main event orchestrating the repulsive response.
authors.affiliation: Department of Biochemical Sciences, University of Florence, Via le Morgagni 50, Florence 50134, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Parri
authors.forename: Francesca
authors.initials: F
authors.lastname: Buricchi
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Taddei
authors.forename: Elisa
authors.initials: E
authors.lastname: Giannoni
authors.forename: Giovanni
authors.initials: G
authors.lastname: Raugei
authors.forename: Giampietro
authors.initials: G
authors.lastname: Ramponi
authors.forename: Paola
authors.initials: P
authors.lastname: Chiarugi
mesh_terms: D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D036382:Ephrin-A1 / Q000502:physiology*; D006801:Humans; D007668:Kidney / Q000166:cytology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008970:Molecular Weight; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D036104:Receptor, EphA2 / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
chemical_list: D036382:Ephrin-A1; D014443:Tyrosine; D036104:Receptor, EphA2; D020929:Mitogen-Activated Protein Kinase Kinases; D017027:Protein Tyrosine Phosphatases