Activating mutations in MEK1 enhance homodimerization and promote tumorigenesis

Autor(en)

Jimin Yuan, Wan Hwa Ng, Zizi Tian, Jiajun Yap, Manuela Baccarini, Zhongzhou Chen, Jiancheng Hu

Abstrakt

RAS-RAF-MEK-ERK signaling has a well-defined role in cancer biology. Although aberrant pathway activation occurs mostly upstream of the kinase MEK, mutations in MEK are prevalent in some cancer subsets. Here, we found that cancer-related, activating mutations in MEK can be classified into two groups: those that relieve inhibitory interactions with the helix A region and those that are in-frame deletions of the β3-αC loop, which enhance MEK1 homodimerization. The former, helix A-associated mutants, are inhibited by traditional MEK inhibitors. However, we found that the increased homodimerization associated with the loop-deletion mutants promoted intradimer cross-phosphorylation of the activation loop and conferred differential resistance to MEK inhibitors both in vitro and in vivo. MEK1 dimerization was required both for its activation by the kinase RAF and for its catalytic activity toward the kinase ERK. Our findings not only identify a previously unknown group of MEK mutants and provide insight into some key steps in RAF-MEK-ERK activation but also have implications for the design of therapies targeting RAS-ERK signaling in cancers.

Organisation(en)

Department für Mikrobiologie, Immunbiologie und Genetik

Externe Organisation(en)

National Cancer Centre Singapore, China Agricultural University, National University of Singapore (NUS)

Journal

Science Signaling

Band

11

Anzahl der Seiten

11

ISSN

1945-0877

DOI

https://doi.org/10.1126/scisignal.aar6795

Publikationsdatum

10-2018

Peer-reviewed

Ja

ÖFOS 2012

106023 Molekularbiologie, 106052 Zellbiologie

Schlagwörter

ASJC Scopus Sachgebiete

Molecular Biology, Biochemistry, Cell Biology

Sustainable Development Goals

SDG 3 – Gesundheit und Wohlergehen

Link zum Portal

https://ucrisportal.univie.ac.at/de/publications/1059152c-cbe0-4cf8-99ac-ac7b9a69a1cb