title: Downregulation of Rap1GAP in human tumor cells alters cell/matrix and cell/cell adhesion.
abstract: Rap1GAP expression is decreased in human tumors. The significance of its downregulation is unknown. We show that Rap1GAP expression is decreased in primary colorectal carcinomas. To elucidate the advantages conferred on tumor cells by loss of Rap1GAP, Rap1GAP expression was silenced in human colon carcinoma cells. Suppressing Rap1GAP induced profound alterations in cell adhesion. Rap1GAP-depleted cells exhibited defects in cell/cell adhesion that included an aberrant distribution of adherens junction proteins. Depletion of Rap1GAP enhanced adhesion and spreading on collagen. Silencing of Rap expression normalized spreading and restored E-cadherin, beta-catenin, and p120-catenin to cell/cell contacts, indicating that unrestrained Rap activity underlies the alterations in cell adhesion. The defects in adherens junction protein distribution required integrin signaling as E-cadherin and p120-catenin were restored at cell/cell contacts when cells were plated on poly-l-lysine. Unexpectedly, Src activity was increased in Rap1GAP-depleted cells. Inhibition of Src impaired spreading and restored E-cadherin at cell/cell contacts. These findings provide the first evidence that Rap1GAP contributes to cell/cell adhesion and highlight a role for Rap1GAP in regulating cell/matrix and cell/cell adhesion. The frequent downregulation of Rap1GAP in epithelial tumors where alterations in cell/cell and cell/matrix adhesion are early steps in tumor dissemination supports a role for Rap1GAP depletion in tumor progression.
authors.affiliation: Department of Pharmacology, University of Pennsylvania School of Medicine, 421 Curie Blvd., BRB II/III, Philadelphia, PA 19104-6061, USA.
authors.forename: Oxana M
authors.initials: OM
authors.lastname: Tsygankova
authors.forename: Changqing
authors.initials: C
authors.lastname: Ma
authors.forename: Waixing
authors.initials: W
authors.lastname: Tang
authors.forename: Christopher
authors.initials: C
authors.lastname: Korch
authors.forename: Michael D
authors.initials: MD
authors.lastname: Feldman
authors.forename: Yu
authors.initials: Y
authors.lastname: Lv
authors.forename: Marcia S
authors.initials: MS
authors.lastname: Brose
authors.forename: Judy L
authors.initials: JL
authors.lastname: Meinkoth
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology*; D045744:Cell Line, Tumor / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D015820:Cadherins; D020690:GTPase-Activating Proteins; C484658:RAP1GAP protein, human; D034741:RNA, Small Interfering; D051176:beta Catenin; D019061:src-Family Kinases