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2016 ; 7
(17
): 24063-75
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English Wikipedia
An evolutionarily conserved negative feedback mechanism in the Hippo pathway
reflects functional difference between LATS1 and LATS2
#MMPMID27006470
Park GS
; Oh H
; Kim M
; Kim T
; Johnson RL
; Irvine KD
; Lim DS
Oncotarget
2016[Apr]; 7
(17
): 24063-75
PMID27006470
show ga
The Hippo pathway represses YAP oncoprotein activity through phosphorylation by
LATS kinases. Although variety of upstream components has been found to
participate in the Hippo pathway, the existence and function of negative feedback
has remained uncertain. We found that activated YAP, together with TEAD
transcription factors, directly induces transcription of LATS2, but not LATS1, to
form a negative feedback loop. We also observed increased mRNA levels of Hippo
upstream components upon YAP activation. To reveal the physiological role of this
negative feedback regulation, we deleted Lats2 or Lats1 in the liver-specific
Sav1-knockout mouse model which develops a YAP-induced tumor. Additional deletion
of Lats2 severely enhanced YAP-induced tumorigenic phenotypes in a liver specific
Sav1 knock-out mouse model while additional deletion of Lats1 mildly affected the
phenotype. Only Sav1 and Lats2 double knock-down cells formed larger colonies in
soft agar assay, thereby recapitulating accelerated tumorigenesis seen in vivo.
Importantly, this negative feedback is evolutionarily conserved, as Drosophila
Yorkie (YAP ortholog) induces transcription of Warts (LATS2 ortholog) with
Scalloped (TEAD ortholog). Collectively, we demonstrated the existence and
function of an evolutionarily conserved negative feedback mechanism in the Hippo
pathway, as well as the functional difference between LATS1 and LATS2 in
regulation of YAP.
|Adaptor Proteins, Signal Transducing/genetics/metabolism
[MESH]