T851I mutation of human large tumor suppressor 1 disrupts its kinase activity and tumor-suppressor functions

Aim Large tumor suppressor 1 (LATS1) is a Ser/Thr kinase to mediate Hippo signaling pathway and plays a pivotal role in tumor suppression. By searching the COSMIC database, we found a somatic missense mutation (NM_004690.4:c.2552C>T) of human LATS1 (NP_004681.1:p.851T>I) in two colorectal cancer cell lines, and investigated the role and underlying mechanism of this mutation in the colorectal tumorigenesis. Main methods We performed structural and biochemistry analyses to investigate the role of LATS1 T851I mutation in Hippo signaling activation and used the mouse xenograft model to assess the role of this mutation in the colorectal tumorigenesis. Key findings By structural and biochemistry approaches, we propose that T851 is an active residue other than Ser909 on the activation loop and is essential for LATS1 phosphorylation and kinase activity. We then reveal that T851I mutation in LATS1 not only destabilizes the phospho-Thr1079-LATS1, a prerequisite of LATS1 kinase activity, but also reduces its binding to the downstream effectors, YAP and TAZ. As a result, T851I mutation in LATS1 attenuates Hippo signaling and decreases its tumor-suppressor functions in the colorectal cancer. Significance The present study identifies the T851 as an essential residue for LATS1 kinase activity and uncovers the T851I mutation of LATS1 and consequent Hippo signaling suppression as a hitherto uncharacterized mechanism controlling colorectal tumorigenesis.