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]
- Material Type
- 단행본
- 0016931651
- Date and Time of Latest Transaction
- 20240214100058
- ISBN
- 9798379620899
- DDC
- 574
- Author
- Lopez, Jocelyne.
- Title/Author
- Investigating Novel Roles and Regulation of SPRED Proteins in MAPK Signaling - [electronic resource]
- Publish Info
- [S.l.]: : University of California, San Francisco., 2023
- Publish Info
- Ann Arbor : : ProQuest Dissertations & Theses,, 2023
- Material Info
- 1 online resource(73 p.)
- General Note
- Source: Dissertations Abstracts International, Volume: 84-12, Section: B.
- General Note
- Advisor: Jura, Natalia.
- 학위논문주기
- Thesis (Ph.D.)--University of California, San Francisco, 2023.
- Restrictions on Access Note
- This item must not be sold to any third party vendors.
- Abstracts/Etc
- 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.
- Subject Added Entry-Topical Term
- Biochemistry.
- Subject Added Entry-Topical Term
- Molecular biology.
- Subject Added Entry-Topical Term
- Cellular biology.
- Index Term-Uncontrolled
- Cell signaling
- Index Term-Uncontrolled
- Neurofibromin
- Index Term-Uncontrolled
- MAPK signaling
- Index Term-Uncontrolled
- SPRED proteins
- Added Entry-Corporate Name
- University of California, San Francisco Biochemistry and Molecular Biology
- Host Item Entry
- Dissertations Abstracts International. 84-12B.
- Host Item Entry
- Dissertation Abstract International
- Electronic Location and Access
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- 소장사항
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202402 2024
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