title: Involvement of Tiam1, RhoG and ELMO2/ILK in Rac1-mediated phagocytosis in human trabecular meshwork cells.
abstract: We previously demonstrated that an αvβ5 integrin/FAK- mediated pathway regulated the phagocytic properties of human trabecular meshwork (HTM) cells. Here we demonstrate that this process is mediated by Rac-1 and a previously unreported signaling pathway that utilizes the Tiam1 as well as a novel ILK/RhoG/ELMO2 signaling pathway. Phagocytosis in both a TM-1 cell line and normal HTM cells was mediated by Rac1 and could be significantly decreased by >75% using the Rac1 inhibitor EHop-016. Knockdown of Rac1 in TM-1 cells also inhibited phagocytosis by 40% whereas overexpression of a constitutively active Rac1 or stimulation with PDGF increased phagocytosis by 83% and 32% respectively. Tiam1 was involved in regulating phagocytosis. Knockdown of Tiam1 inhibited phagocytosis by 72% while overexpression of Tiam1 C1199 increased phagocytosis by 75%. Other upstream effectors of Rac1 found to be involved included ELMO2, RhoG, and ILK. Knockdowns of ELMO2, ILK, and RhoG caused a reduction in phagocytosis by 51%, 55% and 46% respectively. In contrast, knockdown of Vav2 and Dock1 or overexpression of Vav2 Y159/172F did not cause a significant change in phagocytosis. These data suggest a novel link between Tiam1 and RhoG/ILK /ELMO2 pathway as upstream effectors of the Rac1-mediated phagocytic process in TM cells.
authors.affiliation: Departments of Pathology & Laboratory Medicine, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Peotter
authors.affiliation: The Waisman Center, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Phillips
authors.affiliation: Departments of Pathology & Laboratory Medicine, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: Tiegang
authors.initials: T
authors.lastname: Tong
authors.affiliation: Departments of Pathology & Laboratory Medicine, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: Kaylee
authors.initials: K
authors.lastname: Dimeo
authors.affiliation: Doheny Eye Institute and Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Gonzalez
authors.affiliation: Departments of Pathology & Laboratory Medicine, University of Wisconsin, Madison, WI 53706, USA; Ophthalmology & Visual Sciences, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Peters
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D010587:Phagocytosis / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D014129:Trabecular Meshwork / Q000166:cytology* / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D000099200:Scaffold Protein ILK
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D020662:Guanine Nucleotide Exchange Factors; D010982:Platelet-Derived Growth Factor; D017346:Protein Serine-Threonine Kinases; D051567:Proto-Oncogene Proteins c-vav; D034741:RNA, Small Interfering; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; D000099200:Scaffold Protein ILK; C486678:ELMO2 protein, human; C087334:TIAM1 protein, human; C093651:VAV2 protein, human; C075397:RHOG protein, human
keywords: Dock180; ELMO2; Glaucoma; ILK; Phagocytosis; Rac1; RhoG; Tiam1; Trabecular meshwork; Vav2