MLK3 limits activated Galphaq signaling to Rho by binding to p63RhoGEF

TY - JOUR

T1 - MLK3 limits activated Galphaq signaling to Rho by binding to p63RhoGEF

AU - Swenson-Fields, Katherine I

AU - Sandquist, Joshua C

AU - Rossol-Allison, Jessica

AU - Blat, Irene C

AU - Wennerberg, Krister

AU - Burridge, Keith

AU - Means, Anthony R

PY - 2008/10/10

Y1 - 2008/10/10

N2 - Mixed lineage kinase 3 (MLK3) is a MAP3K that activates the JNK-dependent MAPK pathways. Here, we show that MLK3 is required for cell migration in a manner independent of its role as a MAP3K or MLK3 kinase activity. Rather, MLK3 functions in a regulated way to limit levels of the activated GTPase Rho by binding to the Rho activator, p63RhoGEF/GEFT, which, in turn, prevents its activation by Galphaq. These findings demonstrate a scaffolding role for MLK3 in controlling the extent of Rho activation that modulates cell migration. Moreover, they suggest that MLK3 functions as a network hub that links a number of signaling pathways.

AB - Mixed lineage kinase 3 (MLK3) is a MAP3K that activates the JNK-dependent MAPK pathways. Here, we show that MLK3 is required for cell migration in a manner independent of its role as a MAP3K or MLK3 kinase activity. Rather, MLK3 functions in a regulated way to limit levels of the activated GTPase Rho by binding to the Rho activator, p63RhoGEF/GEFT, which, in turn, prevents its activation by Galphaq. These findings demonstrate a scaffolding role for MLK3 in controlling the extent of Rho activation that modulates cell migration. Moreover, they suggest that MLK3 functions as a network hub that links a number of signaling pathways.

KW - Cell Line

KW - Cell Movement/physiology

KW - Cytoskeleton/ultrastructure

KW - Focal Adhesions/ultrastructure

KW - GTP-Binding Protein alpha Subunits, Gq-G11/metabolism

KW - Guanine Nucleotide Exchange Factors/metabolism

KW - Humans

KW - In Vitro Techniques

KW - MAP Kinase Kinase Kinases/antagonists & inhibitors

KW - MAP Kinase Signaling System

KW - Models, Biological

KW - Protein Binding

KW - Pseudopodia/ultrastructure

KW - RNA, Small Interfering/genetics

KW - Receptors, G-Protein-Coupled/metabolism

KW - Recombinant Fusion Proteins/metabolism

KW - Rho Guanine Nucleotide Exchange Factors

KW - Serum Response Factor/metabolism

KW - Signal Transduction

KW - rhoA GTP-Binding Protein/metabolism

U2 - 10.1016/j.molcel.2008.09.007

DO - 10.1016/j.molcel.2008.09.007

M3 - Journal article

C2 - 18851832

SN - 1097-2765

VL - 32

SP - 43

EP - 56

JO - Molecular Cell

JF - Molecular Cell

IS - 1

ER -