The first armadillo repeat is involved in the recognition and regulation of β-catenin phosphorylation by protein kinase CK1

被引:34
作者
Bustos, Victor H.
Ferrarese, Anna
Venerando, Andrea
Marin, Oriano
Allende, Jorge E.
Pinna, Lorenzo A.
机构
[1] Univ Chile, Fac Med, ICBM, Cell & Mol Biol Program, Santiago 8380453, Chile
[2] Venetian Inst Mol Med, I-35129 Padua, Italy
[3] Univ Padua, Dept Biol Chem, I-35121 Padua, Italy
[4] Univ Padua, CNR, Inst Neurosci, I-35121 Padua, Italy
关键词
casein kinase 1; Wnt pathway; substrate recruitment; alpha-catenin;
D O I
10.1073/pnas.0609424104
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Multiple phosphorylation of beta-catenin by glycogen synthase kinase 3 (GSK3) in the Wnt pathway is primed by CK1 through phosphorylation of Ser-45, which lacks a typical CK1 canonical sequence. Synthetic pepticles encompassing amino acids 38-64 of beta-catenin are phosphorylated by CK1 on Ser-45 with low affinity (K-m approximate to 1 mM), whereas intact beta-catenin is phosphorylated at Ser-45 with very high affinity (Km approximate to 200 nM). Pepticles extended to include a putative CK1 docking motif (FXXXF) at 70-74 positions or a F74AA mutation in full-length beta-catenin had no significant effect on CK1 phosphorylation efficiency. beta-Catenin C-terminal deletion mutants up to residue 181 maintained their high affinity, whereas removal of the 131-181 fragment, corresponding to the first armadillo repeat, was deleterious, resulting in a 50-fold increase in Km value. Implication of the first armadillo repeat in beta-catenin targeting by CK1 is supported in that the Y142E mutation, which mimics phosphorylation of Tyr-142 by tyrosine kinases and promotes dissociation of beta-catenin from a-catenin, further improves CKII phosphorylation efficiency, lowering the Km value to < 50 nM, approximating the physiological concentration of P-catenin. In contrast, a-catenin, which interacts with the N-terminal region of beta-catenin, prevents Ser-45 phosphorylation of CK1 in a close-dependent manner. Our data show that the integrity of the N-terminal region and the first armadillo repeat are necessary and sufficient for high-affinity phosphorylation by CK1 of Ser-45. They also suggest that beta-catenin association with a-catenin and alpha-catenin phosphorylation by CK1 at Ser-45 are mutually exclusive.
引用
收藏
页码:19725 / 19730
页数:6
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