LKB1-NUAK 通路在控制肌球蛋白磷酸酶复合物和细胞黏附中的新作用。

New roles for the LKB1-NUAK pathway in controlling myosin phosphatase complexes and cell adhesion.

机构信息

MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, UK.

出版信息

Sci Signal. 2010 Mar 30;3(115):ra25. doi: 10.1126/scisignal.2000616.

DOI:10.1126/scisignal.2000616

PMID:20354225

Abstract

The AMPK-related kinases NUAK1 and NUAK2 are activated by the tumor suppressor LKB1. We found that NUAK1 interacts with several myosin phosphatases, including the myosin phosphatase targeting-1 (MYPT1)-protein phosphatase-1beta (PP1beta) complex, through conserved Gly-Ile-Leu-Lys motifs that are direct binding sites for PP1beta. Phosphorylation of Ser(445), Ser(472), and Ser(910) of MYPT1 by NUAK1 promoted the interaction of MYPT1 with 14-3-3 adaptor proteins, thereby suppressing phosphatase activity. Cell detachment induced phosphorylation of endogenous MYPT1 by NUAK1, resulting in 14-3-3 binding to MYPT1 and enhanced phosphorylation of myosin light chain-2. Inhibition of the LKB1-NUAK1 pathway impaired cell detachment. Our data indicate that NUAK1 controls cell adhesion and functions as a regulator of myosin phosphatase complexes. Thus, LKB1 can influence the phosphorylation of targets not only through the AMPK family of kinases but also by controlling phosphatase complexes.

摘要

AMPK 相关激酶 NUAK1 和 NUAK2 被肿瘤抑制因子 LKB1 激活。我们发现 NUAK1 通过保守的 Gly-Ile-Leu-Lys 基序与几种肌球蛋白磷酸酶相互作用，包括肌球蛋白磷酸酶靶向 1（MYPT1）-蛋白磷酸酶 1β（PP1β）复合物，这些基序是 PP1β 的直接结合位点。NUAK1 对 MYPT1 的 Ser(445)、Ser(472)和 Ser(910)的磷酸化促进了 MYPT1 与 14-3-3 衔接蛋白的相互作用，从而抑制了磷酸酶活性。细胞脱离诱导内源性 MYPT1 被 NUAK1 磷酸化，导致 14-3-3 与 MYPT1 结合并增强肌球蛋白轻链-2 的磷酸化。抑制 LKB1-NUAK1 途径会损害细胞脱离。我们的数据表明，NUAK1 控制细胞黏附并作为肌球蛋白磷酸酶复合物的调节剂发挥作用。因此，LKB1 不仅可以通过 AMPK 家族激酶影响靶标的磷酸化，还可以通过控制磷酸酶复合物来影响靶标的磷酸化。