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Investigating Novel Roles and Regulation of SPRED Proteins in MAPK Signaling- [electronic resource]
Investigating Novel Roles and Regulation of SPRED Proteins in MAPK Signaling- [electronic resource]
상세정보
- 자료유형
- 학위논문파일 국외
- 최종처리일시
- 20240214100058
- ISBN
- 9798379620899
- DDC
- 574
- 저자명
- Lopez, Jocelyne.
- 서명/저자
- Investigating Novel Roles and Regulation of SPRED Proteins in MAPK Signaling - [electronic resource]
- 발행사항
- [S.l.]: : University of California, San Francisco., 2023
- 발행사항
- Ann Arbor : : ProQuest Dissertations & Theses,, 2023
- 형태사항
- 1 online resource(73 p.)
- 주기사항
- Source: Dissertations Abstracts International, Volume: 84-12, Section: B.
- 주기사항
- Advisor: Jura, Natalia.
- 학위논문주기
- Thesis (Ph.D.)--University of California, San Francisco, 2023.
- 사용제한주기
- This item must not be sold to any third party vendors.
- 초록/해제
- 요약Sprouty-related EVH-1 domain-containing (SPRED) proteins are a family of proteins that negatively regulate the RAS-MAPK pathway, which is involved in the regulation of the mitogenic response and cell proliferation. However, the mechanism by which these proteins affect RASMAPK signaling has not been fully elucidated. Patients with mutations in SPRED give rise to unique disease phenotypes, thus we hypothesized that distinct interactions across SPRED proteins may account for alternative nodes of regulation. Chapter 2 shows our efforts to characterize the SPRED interactome and evaluate how members of the SPRED family function through unique binding partners, here we performed affinity purification mass spectrometry. We identified 90- kDa ribosomal S6 kinase 2 (RSK2) as a specific interactor of SPRED2, but not SPRED1 or SPRED3. We identified that the N-terminal kinase domain of RSK2 mediates interaction between amino acids 123-201 of SPRED2. Using X-ray crystallography, we determined the structure of the SPRED2-RSK2 complex and identified the SPRED2 motif, F145A, as critical for interaction. Additionally, we found that formation of this interaction is regulated by MAPK signaling events. We also find that that this interaction between SPRED2 and RSK2 has functional consequences, whereby knockdown of SPRED2 resulted in increased phosphorylation of RSK substrates, YB1 and CREB. Furthermore, SPRED2 knockdown hindered phospho-RSK membrane and nuclear subcellular localization. Lastly, we report that disruption of the SPRED2-RSK complex has effects on RAS-MAPK signaling dynamics. Overall, our analysis reveals that members of the SPRED family have unique protein binding partners and describes the molecular and functional determinants of SPRED2-RSK2 complex dynamics.Model organism are important tools to investigate molecular mechanisms in vivo. In effort to evaluate the molecular mechanisms of SPRED2 in vivo, we set out to use a previously published SPRED2 mouse models. However, when undergoing studies, we observed several discrepancies in the mice phenotypes. Chapter 3 is a letter to editor, in response to the discrepancies we observed in these mice.
- 일반주제명
- Biochemistry.
- 일반주제명
- Molecular biology.
- 일반주제명
- Cellular biology.
- 키워드
- Cell signaling
- 키워드
- Neurofibromin
- 키워드
- MAPK signaling
- 키워드
- SPRED proteins
- 기타저자
- University of California, San Francisco Biochemistry and Molecular Biology
- 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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■00520240214100058
■006m o d
■007cr#unu||||||||
■020 ▼a9798379620899
■035 ▼a(MiAaPQ)AAI30318917
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a574
■1001 ▼aLopez, Jocelyne.▼0(orcid)0000-0002-5626-7818
■24510▼aInvestigating Novel Roles and Regulation of SPRED Proteins in MAPK Signaling▼h[electronic resource]
■260 ▼a[S.l.]:▼bUniversity of California, San Francisco. ▼c2023
■260 1▼aAnn Arbor :▼bProQuest Dissertations & Theses, ▼c2023
■300 ▼a1 online resource(73 p.)
■500 ▼aSource: Dissertations Abstracts International, Volume: 84-12, Section: B.
■500 ▼aAdvisor: Jura, Natalia.
■5021 ▼aThesis (Ph.D.)--University of California, San Francisco, 2023.
■506 ▼aThis item must not be sold to any third party vendors.
■520 ▼aSprouty-related EVH-1 domain-containing (SPRED) proteins are a family of proteins that negatively regulate the RAS-MAPK pathway, which is involved in the regulation of the mitogenic response and cell proliferation. However, the mechanism by which these proteins affect RASMAPK signaling has not been fully elucidated. Patients with mutations in SPRED give rise to unique disease phenotypes, thus we hypothesized that distinct interactions across SPRED proteins may account for alternative nodes of regulation. Chapter 2 shows our efforts to characterize the SPRED interactome and evaluate how members of the SPRED family function through unique binding partners, here we performed affinity purification mass spectrometry. We identified 90- kDa ribosomal S6 kinase 2 (RSK2) as a specific interactor of SPRED2, but not SPRED1 or SPRED3. We identified that the N-terminal kinase domain of RSK2 mediates interaction between amino acids 123-201 of SPRED2. Using X-ray crystallography, we determined the structure of the SPRED2-RSK2 complex and identified the SPRED2 motif, F145A, as critical for interaction. Additionally, we found that formation of this interaction is regulated by MAPK signaling events. We also find that that this interaction between SPRED2 and RSK2 has functional consequences, whereby knockdown of SPRED2 resulted in increased phosphorylation of RSK substrates, YB1 and CREB. Furthermore, SPRED2 knockdown hindered phospho-RSK membrane and nuclear subcellular localization. Lastly, we report that disruption of the SPRED2-RSK complex has effects on RAS-MAPK signaling dynamics. Overall, our analysis reveals that members of the SPRED family have unique protein binding partners and describes the molecular and functional determinants of SPRED2-RSK2 complex dynamics.Model organism are important tools to investigate molecular mechanisms in vivo. In effort to evaluate the molecular mechanisms of SPRED2 in vivo, we set out to use a previously published SPRED2 mouse models. However, when undergoing studies, we observed several discrepancies in the mice phenotypes. Chapter 3 is a letter to editor, in response to the discrepancies we observed in these mice.
■590 ▼aSchool code: 0034.
■650 4▼aBiochemistry.
■650 4▼aMolecular biology.
■650 4▼aCellular biology.
■653 ▼aCell signaling
■653 ▼aNeurofibromin
■653 ▼aMAPK signaling
■653 ▼aSPRED proteins
■690 ▼a0487
■690 ▼a0307
■690 ▼a0379
■71020▼aUniversity of California, San Francisco▼bBiochemistry and Molecular Biology.
■7730 ▼tDissertations Abstracts International▼g84-12B.
■773 ▼tDissertation Abstract International
■790 ▼a0034
■791 ▼aPh.D.
■792 ▼a2023
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T16931651▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
■980 ▼a202402▼f2024
