Hippo pathway-dependent and -independent roles of RASSF6.
The Hippo pathway restricts cell growth and proliferation and promotes apoptosis to control organ size. The Drosophila melanogaster isoform of RASSF (Ras association domain family; dRASSF) antagonizes proapoptotic Hippo signaling by inhibiting the binding of the adaptor protein Salvador to the kinase Hippo. Paradoxically, however, dRASSF also functions as a tumor suppressor. In mammals, RASSF1A induces apoptosis by stimulating the mammalian Ste20-like kinases (MSTs) 1 and 2, which are Hippo homologs. Here, we characterize the interaction between MST2 and another mammalian RASSF isoform, RASSF6. When bound to MST2, RASSF6 inhibited MST2 activity to antagonize Hippo signaling. However, RASSF6 caused apoptosis when released from activated MST2 in a manner dependent on WW45, the mammalian Salvador homolog. Thus, RASSF6 antagonizes Hippo signaling and mediates apoptosis through a pathway that is parallel to the canonical Hippo pathway. Our findings suggest that activation of MST2 causes apoptosis through the Hippo pathway, as well as through a RASSF6-mediated pathway.
Department of Medical Biochemistry, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
Mitsunobu
M
Ikeda
Akira
A
Kawata
Misa
M
Nishikawa
Yuko
Y
Tateishi
Masato
M
Yamaguchi
Kentaro
K
Nakagawa
Susumu
S
Hirabayashi
Yijun
Y
Bao
Shiho
S
Hidaka
Yukio
Y
Hirata
Yutaka
Y
Hata
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D002522:Chlorocebus aethiops; D004247:DNA / Q000235:genetics; D029721:Drosophila Proteins / Q000378:metabolism / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008954:Models, Biological; D020559:Monomeric GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D046912:Multiprotein Complexes; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017434:Protein Structure, Tertiary; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000090742:Serine-Threonine Kinase 3; D015398:Signal Transduction / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D020798:Two-Hybrid System Techniques; D000099317:Hippo Kinases
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004247:DNA; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D020559:Monomeric GTP-Binding Proteins; D046912:Multiprotein Complexes; D017346:Protein Serine-Threonine Kinases; D011993:Recombinant Fusion Proteins; D000090742:Serine-Threonine Kinase 3; D025521:Tumor Suppressor Proteins; C428449:MOAP1 protein, human; C517506:RASSF protein, Drosophila; C519911:RASSF6 protein, human; C415864:SAV1 protein, human; C092745:LATS1 protein, human; C406449:LATS2 protein, human; C097835:STK3 protein, human; D000099317:Hippo Kinases; C491614:STK38 protein, human; C496014:STK38L protein, human; C499474:hpo protein, Drosophila