title: RhoA/phosphatidylinositol 3-kinase/protein kinase B/mitogen-activated protein kinase signaling after growth arrest-specific protein 6/mer receptor tyrosine kinase engagement promotes epithelial cell growth and wound repair via upregulation of hepatocyte growth factor in macrophages.
abstract: Growth arrest-specific protein 6 (Gas6)/Mer receptor tyrosine kinase (Mer) signaling modulates cytokine secretion and helps to regulate the immune response and apoptotic cell clearance. Signaling pathways that activate an epithelial growth program in macrophages are still poorly defined. We report that Gas6/Mer/RhoA signaling can induce the production of epithelial growth factor hepatic growth factor (HGF) in macrophages, which ultimately promotes epithelial cell proliferation and wound repair. The RhoA/protein kinase B (Akt)/mitogen-activated protein (MAP) kinases, including p38 MAP kinase, extracellular signal-regulated protein kinase, and Jun NH2-terminal kinase axis in RAW 264.7 cells, was identified as Gas6/Mer downstream signaling pathway for the upregulation of HGF mRNA and protein. Conditioned medium from RAW 264.7 cells that had been exposed to Gas6 or apoptotic cells enhanced epithelial cell proliferation of the epithelial cell line LA-4 and wound closure. Cotreatment with an HGF receptor-blocking antibody or c-Met antagonist downregulated this enhancement. Inhibition of Mer with small interfering RNA (siRNA) or the RhoA/Rho kinase pathway by RhoA siRNA or Rho kinase pharmacologic inhibitor suppressed Gas6-induced HGF mRNA and protein expression in macrophages and blocked epithelial cell proliferation and wound closure induced by the conditioned medium. Our data provide evidence that macrophages can be reprogrammed by Gas6 to promote epithelial proliferation and wound repair via HGF, which is induced by the Mer/RhoA/Akt/MAP kinase pathway. Thus, defects in Gas6/Mer/RhoA signaling in macrophages may delay tissue repair after injury to the alveolar epithelium.
authors.affiliation: Department of Physiology (Y.-J.L., H.-J.P, S.-Y.W., J.L.K.), Department of Pharmacology (E.-M.P.), Department of Microbiology A (S.-Y.W.), and Tissue Injury Defense Research Center (H.-J.P., S.-Y.W., E.-M.P., J.L.K.), Global Top5 Research Program (J.L.K.), School of Medicine, Ewha Womans University, Seoul, Korea.
authors.forename: Ye-Ji
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Department of Physiology (Y.-J.L., H.-J.P, S.-Y.W., J.L.K.), Department of Pharmacology (E.-M.P.), Department of Microbiology A (S.-Y.W.), and Tissue Injury Defense Research Center (H.-J.P., S.-Y.W., E.-M.P., J.L.K.), Global Top5 Research Program (J.L.K.), School of Medicine, Ewha Womans University, Seoul, Korea.
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Park
authors.affiliation: Department of Physiology (Y.-J.L., H.-J.P, S.-Y.W., J.L.K.), Department of Pharmacology (E.-M.P.), Department of Microbiology A (S.-Y.W.), and Tissue Injury Defense Research Center (H.-J.P., S.-Y.W., E.-M.P., J.L.K.), Global Top5 Research Program (J.L.K.), School of Medicine, Ewha Womans University, Seoul, Korea.
authors.forename: So-Youn
authors.initials: SY
authors.lastname: Woo
authors.affiliation: Department of Physiology (Y.-J.L., H.-J.P, S.-Y.W., J.L.K.), Department of Pharmacology (E.-M.P.), Department of Microbiology A (S.-Y.W.), and Tissue Injury Defense Research Center (H.-J.P., S.-Y.W., E.-M.P., J.L.K.), Global Top5 Research Program (J.L.K.), School of Medicine, Ewha Womans University, Seoul, Korea.
authors.forename: Eun-Mi
authors.initials: EM
authors.lastname: Park
authors.affiliation: Department of Physiology (Y.-J.L., H.-J.P, S.-Y.W., J.L.K.), Department of Pharmacology (E.-M.P.), Department of Microbiology A (S.-Y.W.), and Tissue Injury Defense Research Center (H.-J.P., S.-Y.W., E.-M.P., J.L.K.), Global Top5 Research Program (J.L.K.), School of Medicine, Ewha Womans University, Seoul, Korea jihee@ewha.ac.kr.
authors.forename: Jihee Lee
authors.initials: JL
authors.lastname: Kang
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D019169:Jurkat Cells; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D058539:Phosphatidylinositol 3-Kinase / Q000096:biosynthesis*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D011725:Pyridines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology; D000076202:c-Mer Tyrosine Kinase; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D017228:Hepatocyte Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D058539:Phosphatidylinositol 3-Kinase; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase; D048051:p38 Mitogen-Activated Protein Kinases; D020742:rhoA GTP-Binding Protein; D000099255:Growth Arrest-Specific Protein 6; C066737:RHOA protein, human; C108830:Y 27632; C097072:MERTK protein, human