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Large tumor suppressor 2, LATS2, activates JNK in a kinase-independent mechanism through ASK1 Free
Lauren Rusnak 1,2 , Cong Tang 2,3 , Qi Qi 2 , Xiulei Mo 2 , and Haian Fu 1,2,4,5,*
1 Graduate Program in Cancer Biology, Emory University, Atlanta, GA 30322, USA
2 Department of Pharmacology and Emory Chemical Biology Discovery Center, Emory University, Atlanta, GA 30322, USA
3 The First Affiliated Hospital, Medical School of Xi’an Jiaotong University, Xi’an 710061, China
4 Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA
5 Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, USA
*Correspondence to:* Correspondence to: Haian Fu, E-mail: hfu@emory.edu
J Mol Cell Biol, Volume 10, Issue 6, December 2018, Pages 549-558  https://doi.org/10.1093/jmcb/mjy061
Keyword: ASK1, LATS2, kinase regulation, signal transduction, mitogen-activated protein kinase

Apoptosis signal-regulating kinase 1 (ASK1) is an important mediator of the cell stress response pathways. Because of its central role in regulating cell death, the activity of ASK1 is tightly regulated by protein–protein interactions and post-translational modifications. Deregulation of ASK1 activity has been linked to human diseases, such as neurological disorders and cancer. Here we describe the identification and characterization of large tumor suppressor 2 (LATS2) as a novel binding partner for ASK1. LATS2 is a core kinase in the Hippo signaling pathway and is commonly downregulated in cancer. We found that LATS2 interacts with ASK1 and increases ASK1-mediated signaling to promote apoptosis and activate the JNK mitogen-activated protein kinase (MAPK). This change in MAPK signaling is dependent on the catalytic activity of ASK1 but does not require LATS2 kinase activity. This work identifies a novel role for LATS2 as a positive regulator of the ASK1–MKK–JNK signaling pathway and establishes a kinase-independent function of LATS2 that may be part of the intricate regulatory system for cellular response to diverse stress signals.