期刊
SCIENCE SIGNALING
卷 3, 期 121, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.2000647
关键词
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资金
- NIH [1 R01 GM081635, GM051466, EY006062, EY010291, NS037112, NS049195]
- Pew Charitable Trusts
- National Cancer Institute [GI SPORE P50 CA95103]
- National Institute of General Medical Studies Medical Scientist Training Program [5 T32 GM007347]
- NIH Cancer Biology Training Program [T32 CA09592]
- Molecular Endocrinology Training Program [5 T 32 DK007563]
- American Heart Association Predoctoral Fellowships [0615162B, 0815094E, 0615279B]
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 beta gamma subunits of major families of G proteins in a Xenopus egg extract system that reconstitutes beta-catenin degradation. We found that G alpha(o), G alpha(q), G alpha(i2), and G beta gamma inhibited beta-catenin degradation. G beta(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-beta ARK (C-terminal domain of beta-adrenergic receptor kinase), an inhibitor of G beta gamma, blocked LRP6 activity. Several components of the Wnt-beta-catenin pathway formed a complex: G beta(1 gamma 2), LRP6, GSK3, axin, and dishevelled. We propose that free G beta gamma and G alpha subunits, released from activated G proteins, act cooperatively to inhibit beta-catenin degradation and activate beta-catenin-mediated transcription.
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