Gbetagamma activates GSK3 to promote LRP6-mediated beta-catenin transcriptional activity.
Evidence from Drosophila and cultured cell studies supports a role for heterotrimeric guanosine triphosphate-binding proteins (G proteins) in Wnt signaling. Wnt inhibits the degradation of the transcriptional regulator beta-catenin. We screened the alpha and betagamma subunits of major families of G proteins in a Xenopus egg extract system that reconstitutes beta-catenin degradation. We found that Galpha(o), Galpha(q), Galpha(i2), and Gbetagamma inhibited beta-catenin degradation. Gbeta(1)gamma(2) promoted the phosphorylation and activation of the Wnt co-receptor low-density lipoprotein receptor-related protein 6 (LRP6) by recruiting glycogen synthase kinase 3 (GSK3) to the membrane and enhancing its kinase activity. In both a reporter gene assay and an in vivo assay, c-betaARK (C-terminal domain of beta-adrenergic receptor kinase), an inhibitor of Gbetagamma, blocked LRP6 activity. Several components of the Wnt-beta-catenin pathway formed a complex: Gbeta(1)gamma(2), LRP6, GSK3, axin, and dishevelled. We propose that free Gbetagamma and Galpha subunits, released from activated G proteins, act cooperatively to inhibit beta-catenin degradation and activate beta-catenin-mediated transcription.
Jernigan
Kristin K
KK
Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Cselenyi
Christopher S
CS
Thorne
Curtis A
CA
Hanson
Alison J
AJ
Tahinci
Emilios
E
Hajicek
Nicole
N
Oldham
William M
WM
Lee
Laura A
LA
Hamm
Heidi E
HE
Hepler
John R
JR
Kozasa
Tohru
T
Linder
Maurine E
ME
Lee
Ethan
E
D000818:Animals; D004331:Drosophila melanogaster; D044387:GTP-Binding Protein beta Subunits / Q000235:genetics / Q000378:metabolism*; D044388:GTP-Binding Protein gamma Subunits / Q000235:genetics / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000096:biosynthesis* / Q000235:genetics; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D051552:beta-Adrenergic Receptor Kinases / Q000235:genetics / Q000378:metabolism
D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D026502:LDL-Receptor Related Proteins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051153:Wnt Proteins; D051176:beta Catenin; D051552:beta-Adrenergic Receptor Kinases; D038362:Glycogen Synthase Kinase 3
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