Downregulation of Rap1GAP in Human Tumor Cells Alters Cell/Matrix and Cell/Cell Adhesion
- 1 July 2010
- journal article
- research article
- Published by Taylor & Francis Ltd in Molecular and Cellular Biology
- Vol. 30 (13), 3262-3274
- https://doi.org/10.1128/mcb.01345-09
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, β-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.Keywords
This publication has 57 references indexed in Scilit:
- Downregulation of Rap1GAP through Epigenetic Silencing and Loss of Heterozygosity Promotes Invasion and Progression of Thyroid TumorsCancer Research, 2010
- Loss of Rap1GAP in Papillary Thyroid CancerJournal of Clinical Endocrinology & Metabolism, 2009
- E-cadherin dis-engagement activates the Rap1 GTPaseJournal of Cellular Biochemistry, 2008
- The Diasporin Pathway: a tumor progression-related transcriptional network that predicts breast cancer survivalClinical & Experimental Metastasis, 2008
- Making and breaking contacts: the cellular biology of cadherin regulationCurrent Opinion in Cell Biology, 2007
- Downregulation of Rap1GAP Contributes to Ras TransformationMolecular and Cellular Biology, 2007
- GEFs and GAPs: Critical Elements in the Control of Small G ProteinsCell, 2007
- A Wnt-CKIɛ-Rap1 Pathway Regulates Gastrulation by Modulating SIPA1L1, a Rap GTPase Activating ProteinDevelopmental Cell, 2007
- The Consensus Coding Sequences of Human Breast and Colorectal CancersScience, 2006
- The reliability of assessment of oestrogen receptor expression on needle core biopsy specimens of invasive carcinomas of the breastJournal of Clinical Pathology, 2006