title: An Osteoclastic Transmembrane Protein-Tyrosine Phosphatase Enhances Osteoclast Activity in Part by Dephosphorylating EphA4 in Osteoclasts.
abstract: We have previously shown that PTP-oc is an enhancer of the functional activity of osteoclasts and that EphA4 is a suppressor. Here, we provide evidence that PTP-oc enhances osteoclast activity in part through inactivation of EphA4 by dephosphorylating key phosphotyrosine (pY) residues of EphA4. We show that EphA4 was pulled down by the PTP-oc trapping mutant but not by the wild-type (WT) PTP-oc and that transgenic overexpression of PTP-oc in osteoclasts drastically decreased pY602 and pY779 residues of EphA4. Consistent with the previous findings that EphA4 deficiency increased pY173-Vav3 level (Rac-GTP exchange factor [GEF]) and enhanced bone resorption activity of osteoclasts, reintroduction of WT-Epha4 in Epha4 null osteoclasts led to ∼50% reduction in the pY173-Vav3 level and ∼2-fold increase in bone resorption activity. Overexpression of Y779F-Epha4 mutant in WT osteoclasts markedly increased in pY173-Vav3 and reduced bone resorption activity, but overexpression of Y602F-Epha4 mutant had no effect, suggesting that pY779 residue plays an important role in the EphA4-mediated suppression of osteoclast activity. Deficient EphA4 in osteoclasts has been shown to up-regulate Rac-GTPase and down-regulate Rho-GTPase. PTP-oc overexpression in osteoclasts also increased the GTP-Rac level to 300% of controls, but decreased the GTP-Rho level to ∼50% of controls. PTP-oc overexpression or deficient Epha4 each also reduced pY87-Ephexin level, which is a Rho GEF. Thus, PTP-oc may differentially regulate Rac signaling versus Rho signaling through dephosphorylation of EphA4, which has shown to have opposing effects on Rac-GTPase versus Rho-GTPase through differential regulation of Vav3 versus Ephexin.
authors: Musculoskeletal Disease Center, Jerry L. Pettis Memorial VA Medical Center, Loma Linda, California, 92357.|Department of Medicine, Loma Linda University School of Medicine, Loma Linda, California, 92350.|Departments of Biochemistry, Loma Linda University School of Medicine, Loma Linda, California, 92350.
authors: Kin-Hing William
authors: KH
authors: Lau
authors: Musculoskeletal Disease Center, Jerry L. Pettis Memorial VA Medical Center, Loma Linda, California, 92357.
authors: Mehran
authors: M
authors: Amoui
authors: Musculoskeletal Disease Center, Jerry L. Pettis Memorial VA Medical Center, Loma Linda, California, 92357.
authors: Virginia
authors: V
authors: Stiffel
authors: Musculoskeletal Disease Center, Jerry L. Pettis Memorial VA Medical Center, Loma Linda, California, 92357.|Department of Medicine, Loma Linda University School of Medicine, Loma Linda, California, 92350.
authors: Shin-Tai
authors: ST
authors: Chen
authors: Musculoskeletal Disease Center, Jerry L. Pettis Memorial VA Medical Center, Loma Linda, California, 92357.|Department of Medicine, Loma Linda University School of Medicine, Loma Linda, California, 92350.
authors: Matilda H-C
authors: MH
authors: Sheng
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010010:Osteoclasts / Q000502:physiology*; D010766:Phosphorylation; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000737:chemistry / Q000378:metabolism*; D036122:Receptor, EphA4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D014443:Tyrosine; D036122:Receptor, EphA4; D054558:Protein Tyrosine Phosphatases, Non-Receptor
keywords: EPHEXIN; EphA4 RECEPTOR; OSTEOCLASTS; PROTEIN-TYROSINE PHOSPHATASE; Rho GTPASES; Vav3