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The Glycosyltransferase Alpha-1,3-Mannosyltransferase (ALG3) Is an AKT Substrate that Regulates Protein N-Glycosylation in Breast Cancer Cells
The Glycosyltransferase Alpha-1,3-Mannosyltransferase (ALG3) Is an AKT Substrate that Regulates Protein N-Glycosylation in Breast Cancer Cells
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20250211151427
- ISBN
- 9798382776224
- DDC
- 574
- 서명/저자
- The Glycosyltransferase Alpha-1,3-Mannosyltransferase (ALG3) Is an AKT Substrate that Regulates Protein N-Glycosylation in Breast Cancer Cells
- 발행사항
- [Sl] : Harvard University, 2024
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- 형태사항
- 198 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 85-12, Section: B.
- 주기사항
- Advisor: Toker, Alex.
- 학위논문주기
- Thesis (Ph.D.)--Harvard University, 2024.
- 초록/해제
- 요약The PI3K/AKT signaling pathway is frequently dysregulated in cancer and controls critical cellular processes such as survival, proliferation, metabolism and growth. Additionally, protein glycosylation is essential for proper protein folding and is also frequently deregulated in cancer. Cancer cells require increased protein folding capacity to sustain high proliferation rates. The glycosyltransferase alpha-1,3- mannosyltransferase (ALG3) catalyzes the addition of mannose units to an N-glycan precursor during glycan biosynthesis. ALG3 is a rate-limiting enzyme during glycan biosynthesis in the endoplasmic reticulum.Using in vitro approaches and cell-based assays, we discovered that in breast cancer cells ALG3 functions downstream of the PI3K pathway, and is directly phosphorylated by AKT at Ser11/Ser13. This represents a direct link between PI3K/AKT oncogenic signaling and protein glycosylation. Additionally, we found that the ALG3 gene resides proximal to the PIK3CA gene in the 3q26 amplicon. Consequently, PIK3CA and ALG3 are co-amplified in both lung, breast and ovarian carcinomas. Using cell-based assays, we found that depletion of ALG3 leads to improper glycan formation, induces ER stress and reduces proliferation of breast cancer cells. We further used lectin staining approaches to reveal the functional consequence of PI3K/AKT-mediated regulation of ALG3 function, including the proper folding and surface expression of receptor tyrosine kinases.The studies outlined in this thesis support a model in which in normal cell physiology, growth factor stimulation of the PI3K/AKT pathway leads to phosphorylation of ALG3 at Ser11/Ser13 to facilitate the rate of protein N-glycosylation. Similarly, we further propose a model in which the demands of a rapidly proliferating cancer cell are in part mediated by increased proper protein folding facilitated by ALG3 regulation by hyperactive PI3K/AKT. Consequently, depletion of ALG3 leads to improper glycan formation, proteins misfolding and induction of ER stress and the unfolded protein response. Collectively, these findings advance our understanding of the regulation of N-glycosylation by oncogene-driven signaling and its role in cancer progression, and in turn pave the way for exploring future combination strategies targeting PI3K/AKT and protein glycosylation.
- 일반주제명
- Cellular biology
- 일반주제명
- Biology
- 일반주제명
- Biochemistry
- 일반주제명
- Oncology
- 키워드
- Cancer
- 키워드
- Glycosylation
- 키워드
- Phosphorylation
- 기타저자
- Harvard University Medical Sciences
- 기본자료저록
- Dissertations Abstracts International. 85-12B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■020 ▼a9798382776224
■035 ▼a(MiAaPQ)AAI31294864
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a574
■1001 ▼aNavarro, Adrija June.▼0(orcid)0000-0003-0228-4978
■24510▼aThe Glycosyltransferase Alpha-1,3-Mannosyltransferase (ALG3) Is an AKT Substrate that Regulates Protein N-Glycosylation in Breast Cancer Cells
■260 ▼a[Sl]▼bHarvard University▼c2024
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2024
■300 ▼a198 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 85-12, Section: B.
■500 ▼aAdvisor: Toker, Alex.
■5021 ▼aThesis (Ph.D.)--Harvard University, 2024.
■520 ▼aThe PI3K/AKT signaling pathway is frequently dysregulated in cancer and controls critical cellular processes such as survival, proliferation, metabolism and growth. Additionally, protein glycosylation is essential for proper protein folding and is also frequently deregulated in cancer. Cancer cells require increased protein folding capacity to sustain high proliferation rates. The glycosyltransferase alpha-1,3- mannosyltransferase (ALG3) catalyzes the addition of mannose units to an N-glycan precursor during glycan biosynthesis. ALG3 is a rate-limiting enzyme during glycan biosynthesis in the endoplasmic reticulum.Using in vitro approaches and cell-based assays, we discovered that in breast cancer cells ALG3 functions downstream of the PI3K pathway, and is directly phosphorylated by AKT at Ser11/Ser13. This represents a direct link between PI3K/AKT oncogenic signaling and protein glycosylation. Additionally, we found that the ALG3 gene resides proximal to the PIK3CA gene in the 3q26 amplicon. Consequently, PIK3CA and ALG3 are co-amplified in both lung, breast and ovarian carcinomas. Using cell-based assays, we found that depletion of ALG3 leads to improper glycan formation, induces ER stress and reduces proliferation of breast cancer cells. We further used lectin staining approaches to reveal the functional consequence of PI3K/AKT-mediated regulation of ALG3 function, including the proper folding and surface expression of receptor tyrosine kinases.The studies outlined in this thesis support a model in which in normal cell physiology, growth factor stimulation of the PI3K/AKT pathway leads to phosphorylation of ALG3 at Ser11/Ser13 to facilitate the rate of protein N-glycosylation. Similarly, we further propose a model in which the demands of a rapidly proliferating cancer cell are in part mediated by increased proper protein folding facilitated by ALG3 regulation by hyperactive PI3K/AKT. Consequently, depletion of ALG3 leads to improper glycan formation, proteins misfolding and induction of ER stress and the unfolded protein response. Collectively, these findings advance our understanding of the regulation of N-glycosylation by oncogene-driven signaling and its role in cancer progression, and in turn pave the way for exploring future combination strategies targeting PI3K/AKT and protein glycosylation.
■590 ▼aSchool code: 0084.
■650 4▼aCellular biology
■650 4▼aBiology
■650 4▼aBiochemistry
■650 4▼aOncology
■653 ▼aAlpha-1,3- mannosyltransferase
■653 ▼aCancer
■653 ▼aGlycosylation
■653 ▼aPhosphorylation
■653 ▼aOncogenic signaling
■690 ▼a0379
■690 ▼a0306
■690 ▼a0487
■690 ▼a0992
■71020▼aHarvard University▼bMedical Sciences.
■7730 ▼tDissertations Abstracts International▼g85-12B.
■790 ▼a0084
■791 ▼aPh.D.
■792 ▼a2024
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17161660▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
