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Defining the Biochemical Functions of the TSC Complex and Its Regulation of Rheb-mTORC1 Signaling- [electronic resource]
Defining the Biochemical Functions of the TSC Complex and Its Regulation of Rheb-mTORC1 Signaling- [electronic resource]
상세정보
- 자료유형
- 학위논문파일 국외
- 최종처리일시
- 20240214100449
- ISBN
- 9798379613402
- DDC
- 574
- 서명/저자
- Defining the Biochemical Functions of the TSC Complex and Its Regulation of Rheb-mTORC1 Signaling - [electronic resource]
- 발행사항
- [S.l.]: : Harvard University., 2023
- 발행사항
- Ann Arbor : : ProQuest Dissertations & Theses,, 2023
- 형태사항
- 1 online resource(151 p.)
- 주기사항
- Source: Dissertations Abstracts International, Volume: 84-12, Section: B.
- 주기사항
- Advisor: Manning, Brendan D.
- 학위논문주기
- Thesis (Ph.D.)--Harvard University, 2023.
- 사용제한주기
- This item must not be sold to any third party vendors.
- 초록/해제
- 요약Nutrients and growth factors are sensed by a ubiquitous signaling network that converges on the protein kinase complex mechanistic target of rapamycin (mTOR) complex 1 (mTORC1). mTORC1 functions to integrate a diverse set of growth cues to coordinate the important anabolic processes fundamental to cell growth and proliferation. Upstream of mTORC1, growth factor signaling pathways impinge on the tuberous sclerosis complex (TSC) complex, comprised of the tumor suppressors TSC1 and TSC2, and a third component, TBC1D7, to inhibit its ability to regulate the direct mTORC1 activator, Rheb. The pathways that impinge on the TSC complex are comprised of some of the most common oncogenes and tumor suppressors genetically altered in human cancers. Moreover, direct mutations on TSC1 and TSC2 lead to the genetic tumor syndrome tuberous sclerosis complex (TSC) and have also been identified in sporadic cancers. In all these settings, mTORC1 is aberrantly activated and results in uncontrolled cell growth.The TSC complex acts as a GTPase Activating Protein (GAP) to stimulate GTP hydrolysis on Rheb, converting it from its active to inactive form, and this regulatory function is mapped exclusively to a small c-terminal domain on TSC2. Although significant progress has been made towards understanding the canonical GAP domain of TSC2, many longstanding questions underlying the mechanistic function of the TSC complex and its regulation of Rheb remain unanswered. Through mechanistic studies, I have identified a novel binding interaction between the TSC complex and Rheb that occurs outside of the canonical GAP domain of TSC2. I find that the TSC complex preferentially engages Rheb in is inactive form and that this interaction occurs in a highly phosphorylated region of TSC2 containing the most essential growth factor-stimulated phosphorylation sites. Finally, I show that this interaction appears to be important for complete mTORC1 suppression upon growth factor withdrawal from the cell. Collectively, these studies have revealed previously unrecognized regulatory functions of the TSC complex and provide updated molecular details towards our understanding of the rheb-mTORC1 signaling axis in both normal settings and disease.
- 일반주제명
- Molecular biology.
- 일반주제명
- Oncology.
- 일반주제명
- Biochemistry.
- 키워드
- mTORC1 activator
- 키워드
- Rheb
- 키워드
- GAP
- 키워드
- GTP hydrolysis
- 기타저자
- Harvard University Biological Sciences in Public Health
- 기본자료저록
- Dissertations Abstracts International. 84-12B.
- 기본자료저록
- Dissertation Abstract International
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■00520240214100449
■006m o d
■007cr#unu||||||||
■020 ▼a9798379613402
■035 ▼a(MiAaPQ)AAI30491944
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a574
■1001 ▼aLockwood, Sophie Evarts.▼0(orcid)0000-0002-7838-0846
■24510▼aDefining the Biochemical Functions of the TSC Complex and Its Regulation of Rheb-mTORC1 Signaling▼h[electronic resource]
■260 ▼a[S.l.]:▼bHarvard University. ▼c2023
■260 1▼aAnn Arbor :▼bProQuest Dissertations & Theses, ▼c2023
■300 ▼a1 online resource(151 p.)
■500 ▼aSource: Dissertations Abstracts International, Volume: 84-12, Section: B.
■500 ▼aAdvisor: Manning, Brendan D.
■5021 ▼aThesis (Ph.D.)--Harvard University, 2023.
■506 ▼aThis item must not be sold to any third party vendors.
■520 ▼aNutrients and growth factors are sensed by a ubiquitous signaling network that converges on the protein kinase complex mechanistic target of rapamycin (mTOR) complex 1 (mTORC1). mTORC1 functions to integrate a diverse set of growth cues to coordinate the important anabolic processes fundamental to cell growth and proliferation. Upstream of mTORC1, growth factor signaling pathways impinge on the tuberous sclerosis complex (TSC) complex, comprised of the tumor suppressors TSC1 and TSC2, and a third component, TBC1D7, to inhibit its ability to regulate the direct mTORC1 activator, Rheb. The pathways that impinge on the TSC complex are comprised of some of the most common oncogenes and tumor suppressors genetically altered in human cancers. Moreover, direct mutations on TSC1 and TSC2 lead to the genetic tumor syndrome tuberous sclerosis complex (TSC) and have also been identified in sporadic cancers. In all these settings, mTORC1 is aberrantly activated and results in uncontrolled cell growth.The TSC complex acts as a GTPase Activating Protein (GAP) to stimulate GTP hydrolysis on Rheb, converting it from its active to inactive form, and this regulatory function is mapped exclusively to a small c-terminal domain on TSC2. Although significant progress has been made towards understanding the canonical GAP domain of TSC2, many longstanding questions underlying the mechanistic function of the TSC complex and its regulation of Rheb remain unanswered. Through mechanistic studies, I have identified a novel binding interaction between the TSC complex and Rheb that occurs outside of the canonical GAP domain of TSC2. I find that the TSC complex preferentially engages Rheb in is inactive form and that this interaction occurs in a highly phosphorylated region of TSC2 containing the most essential growth factor-stimulated phosphorylation sites. Finally, I show that this interaction appears to be important for complete mTORC1 suppression upon growth factor withdrawal from the cell. Collectively, these studies have revealed previously unrecognized regulatory functions of the TSC complex and provide updated molecular details towards our understanding of the rheb-mTORC1 signaling axis in both normal settings and disease.
■590 ▼aSchool code: 0084.
■650 4▼aMolecular biology.
■650 4▼aOncology.
■650 4▼aBiochemistry.
■653 ▼amTORC1 activator
■653 ▼aTuberous sclerosis complex
■653 ▼aRheb
■653 ▼aGAP
■653 ▼aGTP hydrolysis
■690 ▼a0307
■690 ▼a0992
■690 ▼a0487
■71020▼aHarvard University▼bBiological Sciences in Public Health.
■7730 ▼tDissertations Abstracts International▼g84-12B.
■773 ▼tDissertation Abstract International
■790 ▼a0084
■791 ▼aPh.D.
■792 ▼a2023
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T16932372▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
■980 ▼a202402▼f2024
