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First published online 30 October 2007
doi: 10.1242/jcs.003806

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A novel role for Lsc/p115 RhoGEF and LARG in regulating RhoA activity downstream of adhesion to fibronectin

¹ Department of Cell and Developmental Biology, University of North Carolina, Chapel Hill NC 27599, USA
² Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill NC 27599, USA

^* Author for correspondence (e-mail: keith_burridge{at}med.unc.edu)

Accepted 3 September 2007

Adhesion of cells to extracellular matrix proteins such as fibronectin initiates signaling cascades that affect cell morphology, migration and survival. Some of these signaling pathways involve the Rho family of GTPases, such as Cdc42, Rac1 and RhoA, which play a key role in regulating the organization of the cytoskeleton. Although significant advances have been made in understanding how Rho proteins control cytoskeletal architecture, less is known about the signals controlling activation of the GTPases themselves. The focus of this study was to determine which guanine nucleotide exchange factor(s) are responsible for activation of RhoA downstream of adhesion to fibronectin. Using an affinity pulldown assay for activated exchange factors, we show that the RhoA-specific exchange factors Lsc/p115 RhoGEF and LARG are activated when cells are plated onto fibronectin, but not other exchange factors such as Ect2 or Dbl. Knockdown of Lsc and LARG together significantly decreases RhoA activation and formation of stress fibers and focal adhesions downstream of fibronectin adhesion. Similarly, overexpression of a catalytically inactive mutant of Lsc/p115 RhoGEF inhibits RhoA activity and formation of stress fibers and focal adhesions on fibronectin. These data establish a previously uncharacterized role for the exchange factors Lsc/p115 RhoGEF and LARG in linking fibronectin signals to downstream RhoA activation.

Key words: Lsc, p115 RhoGEF, Leukemia-associated RhoGEF, RhoA, Fibronectin, Guanine nucleotide exchange factors, Extracellular matrix, Stress fibers, Focal adhesions, Cell spreading

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