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Originally published In Press as doi:10.1167/iovs.07-1598 on May 9, 2008
 (Investigative Ophthalmology and Visual Science. 2009;50:462-469.)
© 2009 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.07-1598
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FAK Activation and the Role of Epithelial Membrane Protein 2 (EMP2) in Collagen Gel Contraction

Shawn A. Morales,1,2 Sergey Mareninov,2 Madhuri Wadehra,1 Lily Zhang,1 Lee Goodglick,1 Jonathan Braun,1 and Lynn K. Gordon3,2

1From the Departments of Pathology and Laboratory Medicine and 2Ophthalmology, University of California, Los Angeles, California; and the 3Department of Surgery, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, California.

PURPOSE. Proliferative vitreoretinopathy (PVR) occurs in approximately 10% of patients after retinal detachment. PVR results from a multiphase process that leads to an aberrant wound-healing strategy with contractile cellular forces and tractional retinal detachment (TRD). Epithelial membrane protein (EMP) 2 controls cell surface expression and function of integrin isoforms associated with cellular contraction in many cell types. Since EMP2 is highly expressed in retinal pigment epithelium, this study investigates the role of EMP2 in collagen gel contraction.

METHODS. EMP2 expression was recombinantly modified in the ARPE-19 cell line. Cell surface integrin expression was assessed by flow cytometry. Collagen gel contraction was assessed by using an in vitro assay and the percentage of contraction was quantified. Proliferation and migration were measured by BrdU incorporation and a wound-healing assay, respectively. Cellular invasion was investigated with polycarbonate membranes coated with collagen.

RESULTS. EMP2 expression levels correlated positively with the ability to contract collagen gels. Compared with wild-type ARPE-19 cells, the cells with increased EMP2 expression exhibited enhanced contraction (P = 0.02), and decreased EMP2 expression concomitantly resulted in decreased contraction (P = 0.002). EMP2 overexpression resulted in reduced proliferation, migration, and integrin {alpha}1 and {alpha}2 integrin expression. EMP2 overexpression was associated with a 70% increase in FAK activation (P = 0.0003) and relative resistance of gel contraction to inhibitors of FAK/Src activation.

CONCLUSIONS. ARPE-19-mediated collagen gel contraction is a multistep process that requires integrin ligation and activation of the FAK/Src complex. EMP2 positively modulates collagen gel contraction by ARPE-19 cells through increased FAK activation.






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