MLK3 limits activated Galphaq signaling to Rho by binding to p63RhoGEF.
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.
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Katherine I
KI
Swenson-Fields
Joshua C
JC
Sandquist
Jessica
J
Rossol-Allison
Irene C
IC
Blat
Krister
K
Wennerberg
Keith
K
Burridge
Anthony R
AR
Means
D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D003599:Cytoskeleton / Q000648:ultrastructure; D022001:Focal Adhesions / Q000648:ultrastructure; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D011485:Protein Binding; D011554:Pseudopodia / Q000648:ultrastructure; D034741:RNA, Small Interfering / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors; D026362:Serum Response Factor / Q000378:metabolism; D015398:Signal Transduction; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020662:Guanine Nucleotide Exchange Factors; D020930:MAP Kinase Kinase Kinases; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins; D064067:Rho Guanine Nucleotide Exchange Factors; D026362:Serum Response Factor; D020742:rhoA GTP-Binding Protein; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C475063:ARHGEF25 protein, human; C476858:SRF protein, human; C066737:RHOA protein, human