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초청세미나

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종양연구소 초청세미나 (2017.08.28)
종양연구소 조회수:1105
2017-07-17 10:47:39

충북대학교 종양연구소에서 다음과 같이 초청세미나를 개최하오니 많은 참여 부탁드립니다.

                                  -    다    음   -

 

1. 연 자  :  조 익 훈 교수 (서울대학교)

 

2. 일 시  :  2017년 08월 28일 (월)  오후 4시

 

3. 연 제  :  Functional analysis of novel regulators of Hippo signaling pathway.

 

4. 장 소  :  종양연구소 세미나실 104호 

 

5. 발 표 내 용

 

Hippo signaling controls organ size by regulating cell proliferation and apoptosis. Yes-associated protein (YAP) is a key downstream effector of Hippo signaling and LATS-mediated phosphorylation of YAP at Ser127 inhibits its nuclear localization and transcriptional activity. Here, we report that Nemo-like kinase (NLK) phosphorylates YAP at Ser128 both in vitro and in vivo, which blocks interaction with 14-3-3 and enhances its nuclear localization. Depletion of NLK increases YAP phosphorylation at Ser127 and reduces YAP-mediated reporter activity. These results suggest that YAP phosphorylation at Ser128 and at Ser127 may be mutually exclusive. We also find that with the increase in cell density, nuclear localization and the level of NLK are reduced, resulting in reduction of YAP phosphorylation at Ser128. Furthermore, knockdown of Nemo (the Drosophila NLK) in fruit fly wing imaginal discs results in reduced expression of the Yorkie (the Drosophila YAP) target genes expanded and DIAP1, while Nemo overexpression reciprocally increased the expression. Overall, our data suggest that NLK/Nemo acts as an endogenous regulator of Hippo signaling by controlling nuclear localization and activity of YAP/Yorkie.

Itch, a HECT class E3 ubiquitin ligase, is known to regulate the stability of the large tumor suppressor 1 (LATS1) which is a key player of Hippo signaling pathway. LATS1 plays important roles in the control of organ size by regulating cell proliferation and apoptosis via modulating the phosphorylation/level of the Yes-associated protein (YAP)/TAZ transcription coactivators. Here, we report that YOD1, a deubiquitinase, regulates Hippo signaling pathway by controlling the level of Itch. Knockdown of YOD1 reduced the level of Itch, which in turn led to increase and decrease in the levels of LATS1 and TAZ, respectively. Ectopic expression of YOD1 exhibited the opposite results to the knockdown of YOD1. Consistent with these data, the YAP/TAZ mediated reporter activity was down-regulated by knockdown of YOD1. YOD1 can complex with Itch. The ubiquitination status of Itch was regulated by YOD1. Furthermore, YOD1-mediated stabilization of Itch was associated with enhanced cell survival. Interestingly the level of YOD1 is reduced, along with decrease in the levels of Itch and YAP/TAZ, in a high cell density. Overall these data strongly suggest that YOD1 is a noble regulator of Hippo signaling pathway, although the mechanism for the down-regulation of YOD1 in a high cell density needs to be further elucidated.

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