BIRC6 is an isoform-specific E2/E3 Ubiquitin Ligase for KRAS4A- [electronic resource]
BIRC6 is an isoform-specific E2/E3 Ubiquitin Ligase for KRAS4A- [electronic resource]
- 자료유형
- 학위논문파일 국외
- 최종처리일시
- 20240214101514
- ISBN
- 9798380623193
- DDC
- 616.99
- 서명/저자
- BIRC6 is an isoform-specific E2/E3 Ubiquitin Ligase for KRAS4A - [electronic resource]
- 발행사항
- [S.l.]: : New York University., 2023
- 발행사항
- Ann Arbor : : ProQuest Dissertations & Theses,, 2023
- 형태사항
- 1 online resource(163 p.)
- 주기사항
- Source: Dissertations Abstracts International, Volume: 85-04, Section: B.
- 주기사항
- Advisor: Philips, Mark Reid.
- 학위논문주기
- Thesis (Ph.D.)--New York University, 2023.
- 사용제한주기
- This item must not be sold to any third party vendors.
- 초록/해제
- 요약RAS proteins are small, membrane-associated GTPases that act as molecular switches to transduce signals from membrane receptors to intracellular signaling cascades. When activated, RAS proteins interact with an array of effector proteins to coordinate various cellular processes, including metabolism, apoptosis, and cell cycle, to prevent cell death and stimulate cellular proliferation. The human genome contains three RAS genes (HRAS, KRAS, and NRAS) that encode four RAS proteins. Gain-of-function mutations in KRAS are the most prevalent oncogenes in human cancers. The KRAS pre-mRNA is alternatively spliced to generate two isoforms: KRAS4A and KRAS4B. KRAS4B is largely considered the primary RAS isoform, and little is known about the unique properties of KRAS4A relative to other RAS isoforms. However, emerging evidence for KRAS4A expression in tumors and splice variant-specific interactions and functions have sparked interest in this gene product. To further understand the unique roles and functions of KRAS4A, we have determined the unique protein interactomes of KRAS4A and KRAS4B by TurboID proximity biotinylation identification. Using this strategy, we identified baculoviral inhibitor of apoptosis repeat-containing protein 6 (BIRC6) as a KRAS4A-specific protein interaction. We have determined that KRAS4A binds the N-terminal substrate-binding module of BIRC6 in a GTP- and palmitoylation-dependent manner and that this interaction likely occurs on the Golgi, which is the first time KRAS4A has been reported to localize to this compartment. We discovered that the interaction with BIRC6 leads to mono- and diubiquitination of KRAS4A, making BIRC6 the first E3 ubiquitin ligase identified to deposit these ubiquitin marks on KRAS proteins. Finally, we have determined that overexpression of BIRC6 enhances KRAS4A binding to RAF1, suggesting that BIRC6-mediated ubiquitination of KRAS4A stimulates its ability to bind effector proteins. Overall, these results identify BIRC6 as a regulator of KRAS4A and suggest a novel role for BIRC6 in regulating MAPK biology.
- 일반주제명
- Pathology.
- 일반주제명
- Oncology.
- 일반주제명
- Cellular biology.
- 일반주제명
- Biochemistry.
- 기타저자
- New York University Basic Medical Science
- 기본자료저록
- Dissertations Abstracts International. 85-04B.
- 기본자료저록
- Dissertation Abstract International
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- 로그인 후 원문을 볼 수 있습니다.