Characterization of two Mst1‐deficient mouse models

Abstract

Mammalian sterile 20-like kinase 1 (Mst1) is a ubiquitously expressed serine/threonine kinase belonging to the family of Sterile 20-like kinases. MST1 has been inferred to play important roles in apoptosis and in the inhibition of proliferation in mammalian cells. Here, we describe the genetic characterization of Mst1-deficient mice produced by two distinct gene-trap insertions. Animals generated from clone RRT293 exhibit transmission ratio distortion favoring the mutated allele and is amplified with each generation. Inexplicably, while the mutated allele is favored for transmission, its homozygosity is embryonic lethal. By contrast, animals generated from the second Mst1 gene-trap clone, AJ0315, do not show any gross abnormalities. We find that the discrepancy in phenotype is most likely attributable to a second insertion in the RRT293 clone. Thus, a mutation in Mst1 alone does not affect survival. Our results set the stage for identification of the lethal second-site mutation that is paradoxically favored for transmission.

TRIM21 is critical in regulating hepatocellular carcinoma growth and response to therapy by altering the MST1/YAP pathway

“…MST1 inhibits YAP activation and acts as a tumor suppressor 12 . Genetic knockout MST1 results in hyperactivation of YAP and tumorigenesis 15,51 . How MST1 exerts its tumor suppressor function in human cancer remains largely unknown.…”

“… 12 Genetic knockout MST1 results in hyperactivation of YAP and tumorigenesis. 15 , 51 How MST1 exerts its tumor suppressor function in human cancer remains largely unknown. Previous study has shown that MST1 promotes cancer growth by inhibiting AMPK‐SIRT3 mediated mitochondrial fission for cell death.…”

The DeMSTification of Mammalian Ste20 Kinases

“…Hypermethylation of the Mst1 and Mst2 promoters have been shown to inhibit the WW45-Rassf1-Mst pathway in human sarcomas [48] and loss of cytoplasmic Mst1 has been reported to be a marker for tumor progression in colorectal cancer, suggesting that Mst1 can function as a tumor suppressor [49]. However, the Mst1 knockout mouse is reported to have a surprisingly mild phenotype and does not appear, on its own, to have tumor suppressor function [25,50]. Whether Mst2, which can replace Hippo function in flies, will have such activity is not known.…”

The Hippo Tumor Suppressor Pathway (YAP/TAZ/TEAD/MST/LATS) and EGFR-RAS-RAF-MEK in cancer metastasis

“…Since MST and LATS have significant effects on the living organism, they are only epistatically associated with YAP. 58 , 59 , 60 , 61 , 62 , 63 , 64 One of the conserved proteins in the Hippo pathway is the Ajuba Scaffold protein, which interacts with LATS kinases and SAV, limiting centromere signaling and decreasing inhibition of YAP phosphorylation. 65 EFGR-RAS signaling activates MAPKs (ERK and JNK), both of which MAPKs phosphorylate Ajuba proteins, increase LATS binding, and YAP transcriptional activation.…”