Axin-mediated CKI phosphorylation of β-catenin at Ser 45: a molecular switch for the Wnt pathway

Genes and Development - Tập 16 Số 9 - Trang 1066-1076 - 2002
Sharon Amit1, Ada Hatzubai1, Yaara Birman1, Jens Andersen2, Etti Ben-Shushan1, Matthias Mann2, Yinon Ben‐Neriah1, Irit Alkalay1
1The Lautenberg Center for Immunology, The Hebrew University-Hadassah Medical School Jerusalem 91120 Israel
2Protein Interaction Laboratory, University of Southern Denmark, DK-5230 Odense M, Denmark

Tóm tắt

The Wnt pathway controls numerous developmental processes via the β-catenin–TCF/LEF transcription complex. Deregulation of the pathway results in the aberrant accumulation of β-catenin in the nucleus, often leading to cancer. Normally, cytoplasmic β-catenin associates with APC and axin and is continuously phosphorylated by GSK-3β, marking it for proteasomal degradation. Wnt signaling is considered to prevent GSK-3β from phosphorylating β-catenin, thus causing its stabilization. However, the Wnt mechanism of action has not been resolved. Here we study the regulation of β-catenin phosphorylation and degradation by the Wnt pathway. Using mass spectrometry and phosphopeptide-specific antibodies, we show that a complex of axin and casein kinase I (CKI) induces β-catenin phosphorylation at a single site: serine 45 (S45). Immunopurified axin and recombinant CKI phosphorylate β-catenin in vitro at S45; CKI inhibition suppresses this phosphorylation in vivo. CKI phosphorylation creates a priming site for GSK-3β and is both necessary and sufficient to initiate the β-catenin phosphorylation–degradation cascade. Wnt3A signaling and Dvl overexpression suppress S45 phosphorylation, thereby precluding the initiation of the cascade. Thus, a single, CKI-dependent phosphorylation event serves as a molecular switch for the Wnt pathway.

Từ khóa


Tài liệu tham khảo

10.1093/emboj/16.13.3797

10.1021/cr000110o

10.1016/S0969-2126(01)00679-7

10.1126/science.280.5363.596

10.1016/S0092-8674(00)00122-7

10.1016/S0925-4773(99)00046-5

Chijiwa, 1989, A newly synthesized selective casein kinase I inhibitor, N-(2-aminoethyl)-5-chloroisoquinoline-8-sulfonamide, and affinity purification of casein kinase I from bovine testis., J. Biol. Chem., 264, 4924, 10.1016/S0021-9258(18)83679-1

10.1038/35096075

10.1016/S0092-8674(01)00374-9

10.1074/jbc.M005342200

10.1016/S0955-0674(99)80031-3

10.1083/jcb.148.4.691

10.1093/hmg/10.7.721

10.1074/jbc.270.25.14875

10.1016/S1097-2765(01)00253-2

10.1074/jbc.M109462200

10.1073/pnas.032468199

10.1016/0092-8674(81)90021-0

10.1016/S0960-9822(98)70226-X

10.1016/S0960-9822(99)80091-8

10.1016/S0092-8674(01)00412-3

10.1074/jbc.M003997200

10.1016/S0959-437X(00)00231-8

10.1093/emboj/17.5.1371

10.1126/science.1651562

10.1074/jbc.M103555200

Kishida, 1999, DIX domains of Dvl and axin are necessary for protein interactions and their ability to regulate β-catenin stability., Mol. Cell. Biol., 19, 4414, 10.1128/MCB.19.6.4414

10.1093/emboj/18.9.2401

10.1073/pnas.93.16.8455

10.1038/sj.onc.1202653

10.1083/jcb.200102074

10.1074/jbc.274.30.21464

10.1093/emboj/18.15.4233

10.1016/S0092-8674(02)00685-2

10.1006/dbio.2001.0307

10.1126/science.275.5307.1787

10.1126/science.287.5458.1606

10.1038/43830

Polakis, 2000, Wnt signaling and cancer., Genes & Dev., 14, 1837, 10.1101/gad.14.15.1837

10.1101/gad.5.3.381

10.1126/science.275.5307.1790

10.1074/jbc.M105148200

10.1073/pnas.95.6.3020

10.1073/pnas.96.22.12548

10.1016/S1097-2765(00)80446-3

10.1038/73448

10.1046/j.1365-2443.1998.00221.x

10.1093/emboj/18.10.2823

Sparks, 1998, Mutational analysis of the APC/β-catenin/Tcf pathway in colorectal cancer., Cancer Res., 58, 1130

10.1016/S0960-9822(02)70790-2

10.1016/S0959-437X(98)80068-3

10.1101/gad.13.3.270

10.1146/annurev.cellbio.14.1.59

10.1002/1097-0142(20010701)92:1<136::AID-CNCR1301>3.0.CO;2-R

Woodgett, 1990, Molecular cloning and expression of glycogen synthase kinase-3/factor A., EMBO J., 9, 2431, 10.1002/j.1460-2075.1990.tb07419.x

Yamamoto, 1998, Axil, a member of the Axin family, interacts with both glycogen synthase kinase 3β and β-catenin and inhibits axis formation of Xenopus embryos., Mol. Cell. Biol., 18, 2867, 10.1128/MCB.18.5.2867

10.1074/jbc.274.16.10681

Yanagawa, S., Matsuda, Y., Lee, J., Matsubayashi, H., Sese, S., Kadowaki, T., and Ishimoto, A. 2002. Casein Kinase I phosphorylates the armadillo protein and induces its degradation in Drosophila. EMBO J. (in press)..

10.1038/25159

10.1016/S0092-8674(00)80324-4

Thông tin
Thông tin xuất bản

Genes and Development

Tập 16 Số 9

1066-1076

Thông tin tác giả