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Papers In Press, published online ahead of print March 24, 2003
J. Biol. Chem, 10.1074/jbc.M213066200
Submitted on December 20, 2002
Revised on March 20, 2003
Accepted on March 24, 2003

Serine phosphorylation negatively regulates RhoA in vivo

Shawn M. Ellerbroek, Krister Wennerberg, and Keith Burridge

Cell and Developmental Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599

Corresponding Author: hawkeye{at}med.unc.edu

Previous work indicates that RhoA phosphorylation on ser188 by cAMP or cGMP-dependent kinases (PKA or PKG) inhibits its activity. However, these studies lacked the possibility to directly study phosphorylated RhoA activity in vivo. Therefore, we created RhoA proteins containing phosphomimetic residues in place of the PKA/PKG phosphorylation site. RhoA phosphorylation or phosphomimetic substitution did not affect Rho guanine nucleotide exchange factor (GEF), GTPase activating protein (GAP), or geranylgeranyl transferase activity in vitro, but promoted binding to RhoGDI as measured by exchange factor competition assays. The in vitro similarities between RhoA phosphomimetic proteins and phosphorylated RhoA allowed us to study function of phosphorylated RhoA in vivo. RhoA phosphomimetic proteins display depressed GTP-loading when transiently expressed in NIH 3T3 cells. Stable-expressing RhoA and RhoA(S188A) clones spread significantly slower than mock-transfected or RhoA(S188E) clones. RhoA(S188A) clones were protected from the morphological effects of a cAMP agonist, whereas phosphomimetic clones exhibit stress fiber disassembly similar to control cells. Together, these data provide in vivo evidence that addition of a charged group to Ser188 upon phosphorylation negatively regulates RhoA activity and indicates that this occurs through enhanced RhoGDI interaction rather than direct perturbation of GEF, GAP, or geranylgeranyl transferase activity.


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