(A) study on the role of MAP3K3 in YAP abundance regulation and anticancer drug resistance in cutaneous melanoma cellsYAP의 양적 조절과 피부흑색종 세포의 항암제 내성에서 MAP3K3의 역할에 관한 연구

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The transcription coregulator YAP plays important roles in cancer development and anticancer therapy resistance. Especially, several reports have shown that YAP plays an important role in the cancer progression, lymphatic metastasis, and resistance to BRAF inhibitors in cutaneous melanoma. Cellular YAP activity is determined by a combination of its nuclear localization and protein stability. To date, the regulation of YAP nuclear translocation has been extensively studied as represented by the study of the Hippo-YAP pathway, but the mechanism of YAP stability regulation is incompletely understood. In addition, strategies to block YAP activity in cancer by promoting YAP degradation have not been developed. In this study, I provide evidence that MAP3K3, an atypical MAP kinase, is a positive regulator of YAP stability that acts independently of LATS-mediated proteasomal degradation. MAP3K3 phosphorylates YAP at serine 405 and inhibits polyubiquitination of YAP by affecting its interaction with BTRC and FBXW7. Depletion of MAP3K3 promotes p62-mediated lysosomal degradation of YAP. An increase in MAP3K3 expression supports pro-survival activity of YAP in BRAF inhibitor resistant cutaneous melanoma cells. Furthermore, I show that IL-6 establishes a positive feedback loop between MAP3K3 and YAP in cutaneous melanoma cells. Therefore, my work identifies MAP3K3 as a target to overcome BRAF inhibitor resistance in cutaneous melanoma through YAP inhibition.
Advisors
Kim, Joonresearcher김준researcher
Description
한국과학기술원 :의과학대학원,
Publisher
한국과학기술원
Issue Date
2020
Identifier
325007
Language
eng
Description

학위논문(박사) - 한국과학기술원 : 의과학대학원, 2020.2,[iv, 81 p. :]

Keywords

MAP kinase▼aHippo-YAP pathway▼aYAP abundance▼aBRAF inhibitor resistance▼aCutaneous melanoma; MAP 인산화효소▼aHippo-YAP 경로▼aYAP의 양적 조절▼aBRAF 억제제 내성▼a피부흑색종

URI
http://hdl.handle.net/10203/283569
Link
http://library.kaist.ac.kr/search/detail/view.do?bibCtrlNo=907106&flag=dissertation
Appears in Collection
MSE-Theses_Ph.D.(박사논문)
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