TY - JOUR
T1 - The protein tyrosine phosphatase Shp-2 regulates RhoA activity
AU - Schoenwaelder, Simone M.
AU - Petch, Leslie A.
AU - Williamson, David
AU - Shen, Randy
AU - Feng, Gen Sheng
AU - Burridge, Keith
N1 - Funding Information:
We thank B. Kreft, R. Worthylake, S. Sastry and B. Liu (University of North Carolina); S.P. Jackson and N. Barratt (Monash University) for valuable discussion. S.M.S. is the recipient of an NHMRC C.J. Martin postdoctoral fellowship. This work was supported by a National Heart Foundation (Australia) grant G99M 0346 (S.M.S.), and National Institutes of Health grants GM29860, HL45100 (K.B.), and GM53660 and CA78606 (G.S.F.).
PY - 2000/11/30
Y1 - 2000/11/30
N2 - Remodeling of filamentous actin into distinct arrangements is precisely controlled by members of the Rho family of small GTPases [1]. A well characterized member of this family is RhoA, whose activation results in reorganization of the cytoskeleton into thick actin stress fibers terminating in Integrin-rich focal adhesions [2]. Regulation of RhoA is required to maintain adhesion in stationary cells, but is also critical for cell spreading and migration [3]. Despite its biological importance, the signaling events leading to RhoA activation are not fully understood. Several independent studies have implicated tyrosine phosphorylation as a critical event upstream of RhoA [4]. Consistent with this, our recent studies have demonstrated the existence of a protein tyrosine phosphatase (PTPase), sensitive to the dipeptide aldehyde calpeptin, acting upstream of RhoA [5]. Here we identify the SH2 (Src homology region 2)-containing PTPase Shp-2 as a calpeptin-sensitive PTPase, and show that calpeptin interferes with the catalytic activity of Shp-2 in vitro and with Shp-2 signaling in vivo. Finally, we show that perturbation of Shp-2 activity by a variety of genetic manipulations results in raised levels of active RhoA. Together, these studies identify Shp-2 as a PTPase acting upstream of RhoA to regulate its activity and contribute to the coordinated control of cell movement.
AB - Remodeling of filamentous actin into distinct arrangements is precisely controlled by members of the Rho family of small GTPases [1]. A well characterized member of this family is RhoA, whose activation results in reorganization of the cytoskeleton into thick actin stress fibers terminating in Integrin-rich focal adhesions [2]. Regulation of RhoA is required to maintain adhesion in stationary cells, but is also critical for cell spreading and migration [3]. Despite its biological importance, the signaling events leading to RhoA activation are not fully understood. Several independent studies have implicated tyrosine phosphorylation as a critical event upstream of RhoA [4]. Consistent with this, our recent studies have demonstrated the existence of a protein tyrosine phosphatase (PTPase), sensitive to the dipeptide aldehyde calpeptin, acting upstream of RhoA [5]. Here we identify the SH2 (Src homology region 2)-containing PTPase Shp-2 as a calpeptin-sensitive PTPase, and show that calpeptin interferes with the catalytic activity of Shp-2 in vitro and with Shp-2 signaling in vivo. Finally, we show that perturbation of Shp-2 activity by a variety of genetic manipulations results in raised levels of active RhoA. Together, these studies identify Shp-2 as a PTPase acting upstream of RhoA to regulate its activity and contribute to the coordinated control of cell movement.
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U2 - 10.1016/S0960-9822(00)00831-9
DO - 10.1016/S0960-9822(00)00831-9
M3 - Article
C2 - 11114521
AN - SCOPUS:0034735945
SN - 0960-9822
VL - 10
SP - 1523
EP - 1526
JO - Current Biology
JF - Current Biology
IS - 23
ER -