Constitutively active NDR1-PIF kinase functions independent of MST1 and hMOB1 signalling

被引:29
作者
Cook, Dorthe [1 ]
Hoa, Lily Y. [1 ]
Gomez, Valenti [1 ]
Gomez, Marta [1 ]
Hergovich, Alexander [1 ]
机构
[1] UCL, UCL Canc Inst, Tumour Suppressor Signalling Networks Lab, London WC1E 6BT, England
基金
英国生物技术与生命科学研究理事会; 英国惠康基金;
关键词
Intracellular kinase signalling; MST1/STK4; NDR1/STK38; MOB proteins; Hydrophobic motif phosphorylation; Centrosome duplication; NDR-PROTEIN-KINASE; HYDROPHOBIC MOTIF PHOSPHORYLATION; HIPPO PATHWAY; CELL LYMPHOMA; MECHANISM; IDENTIFICATION; ACTIVATION; REGULATORS; STABILITY; APOPTOSIS;
D O I
10.1016/j.cellsig.2014.04.011
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
The human MST1/hMOB1/NDR1 tumour suppressor cascade regulates important cellular processes, such as centrosome duplication. hMOB1/NDR1 complex formation appears to be essential for NDR1 activation by autophosphorylation on Ser281 and hydrophobic motif (HM) phosphorylation at Thr444 by MST1. To dissect these mechanistic relationships in MST1/hMOB1/NDR signalling, we designed NDR1 variants carrying modifications that mimic HM phosphorylation and/or abolish hMOB1/NDR1 interactions. Significantly, the analyses of these variants revealed that NDR1-PIF, an NDR1 variant containing the PRK2 hydrophobic motif, remains hyperactive independent of hMOB1/NDR1-PIF complex formation. In contrast, as reported for the T444A phospho-acceptor mutant, NDR1 versions carrying single phospho-mimicking mutations at the HM phosphorylation site, namely T444D or T444E, do not display increased kinase activities. Collectively, these observations suggest that in cells Thr444 phosphorylation by MST1 depends on the hMOB1/NDR1 association, while Ser281 autophosphorylation of NDR1 can occur independently. By testing centrosome-targeted NDR1 variants in NDR1-or MST1-depleted cells, we further observed that centrosome-enriched NDR1-PIF requires neither hMOB1 binding nor MST1 signalling to function in centrosome overduplication. Taken together, our biochemical and cell biological characterisation of NDR1 versions provides novel unexpected insights into the regulatory mechanisms of NDR1 and NDR1's role in centrosome duplication. (C) 2014 Elsevier Inc. All rights reserved.
引用
收藏
页码:1657 / 1667
页数:11
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