Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression.
Control of organ size by cell proliferation and survival is a fundamental developmental process, and its deregulation leads to cancer. However, the molecular mechanism underlying organ size control remains elusive in vertebrates. In Drosophila, the Hippo (Hpo) signaling pathway controls organ size by both restricting cell growth and proliferation and promoting cell death. Here we investigated whether mammals also require the Hpo pathway to control organ size and adult tissue homeostasis. We found that Mst1 and Mst2, the two mouse homologs of the Drosophila Hpo, control the sizes of some, but not all organs, in mice, and Mst1 and Mst2 act as tumor suppressors by restricting cell proliferation and survival. We show that Mst1 and Mst2 play redundant roles, and removal of both resulted in early lethality in mouse embryos. Importantly, tumors developed in the liver with a substantial increase of the stem/progenitor cells by 6 months after removing Mst1 and Mst2 postnatally. We show that Mst1 and Mst2 were required in vivo to control Yap phosphorylation and activity. Interestingly, apoptosis induced by TNFalpha was blocked in the Mst1 and Mst2 double-mutant cells both in vivo and in vitro. As TNFalpha is a pleiotropic inflammatory cytokine affecting most organs by regulating cell proliferation and cell death, resistance to TNFalpha-induced cell death may also contribute significantly to tumor formation in the absence of Mst1 and Mst2.
Song
Hai
H
Genetic Disease Research Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA.
Mak
Kinglun Kingston
KK
Topol
Lilia
L
Yun
Kangsun
K
Hu
Jianxin
J
Garrett
Lisa
L
Chen
Yongbin
Y
Park
Ogyi
O
Chang
Jia
J
Simpson
R Mark
RM
Wang
Cun-Yu
CY
Gao
Bin
B
Jiang
Jin
J
Yang
Yingzi
Y
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D018507:Gene Expression Regulation, Developmental; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000201:enzymology* / Q000254:growth & development*; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D051379:Mice; D009154:Mutation; D009929:Organ Size; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D000090742:Serine-Threonine Kinase 3; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099317:Hippo Kinases
D017228:Hepatocyte Growth Factor; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000090742:Serine-Threonine Kinase 3; D014409:Tumor Necrosis Factor-alpha; C082332:macrophage stimulating protein; C490818:Stk3 protein, mouse; D000099317:Hippo Kinases