My note on paper: RNF43
Paper: RNF43
(doi: 10.1136/jclinpath-2017-204763)
Gene of the month in the journal of clinical pathology
Only point out the detail I am interested
Abstract;
RNF43
1.function as tumor suppressor
2.negative feedback to wnt/beta-catenin
3.no RNF43 - no degradation of Frizzled and enhance the wnt/b-catenin signaling pw
Introduction part;
ZNRF3 -- Zinc And Ring Finger 3
--moderate identity 39% with RNF43
Profile
Human RNF43;
chromosome 17q23.2
11 exons - spanning 60 kb
RNF43 protein domains;
1. signal peptide
2. PA - protease-associated domain
2.1 PA -- putative protein recognition domain in distinctive set of TM ubiquitin ligase
2.2 function endocytic pw and cell surface
PA domain of RN43 requires Dishevelled as adaptor to bind with Frizzled receptor --> undergo ubiquitination
3. Transmembrane
4. RING domain which is part of the E3-ubiquitin ligase
Protein domain of RNF43
Location of RNF43:
1. nucleus of human intestinal crypt
2. nucleus of colon cancer cells
3. inner nuclear membrane
4. nuclear periphery
5. nucleoplasm
6. endoplasmic reticulum
7. surface cell membrane
Expression of RNF43 in normal tissues:
** non-neoplasia organs-high level of duodenum, small bowel, colon, and prostate
RNA-seq from 95 human individuals. RPKM -- reads per kilobase of transcript per million mapped (to normalize the expression level of the genes -- make them enable to be compared)
Functions of RNF43;
1.down regulate the wnt signalling by degrading the Frizzled receptor
2. wnt - glycoprotein; function in cell proliferation, migration, cell fate specification, and polarity formation
wnt can interact:
1. Frizzled of course!
2. lipoprotein receptor-related protein 5/6 (LRP5/6)
all are related to wnt/b-catenin signaling pathway
RNF43 is down-regulated by interacting with Respondin (secreted protein - agonist of wnt) -- forming the complex with leucine-rich repeat containing G protein-coupled receptor 4/5 (LGR4/5) -- cause autoubiquitination.
RNF43 can bind to TCF4 (control the expression level of RNF43) and tight it up to the nuclear membrane.
RNF43 can interact with p53 and suppress transcription activity of p53.
Functions of RNF43 in cancer;
Activation of wnt/b-catenin signaling pw -- cause RNF43 expression -- feed back loop to wnt-receptor degradation --> inactivate the wnt/b-catening pw.
Two possible mechanisms of how RNF43 could be related to the cancer;
1. RNF43 mutation -- lack of degradation of Fz receptor
2. RNF43 mutation caused the release of TCF4 --> the level of TCF4 is related to the carcinogenesis in some cancers
(doi: 10.1136/jclinpath-2017-204763)
Gene of the month in the journal of clinical pathology
Only point out the detail I am interested
Abstract;
RNF43
1.function as tumor suppressor
2.negative feedback to wnt/beta-catenin
3.no RNF43 - no degradation of Frizzled and enhance the wnt/b-catenin signaling pw
Introduction part;
ZNRF3 -- Zinc And Ring Finger 3
--moderate identity 39% with RNF43
Human RNF43;
chromosome 17q23.2
11 exons - spanning 60 kb
RNF43 proteins -- 2 isoforms
1. isoform 1 has 2 variants (shorter and longer) - different in mRNA strands but encoding the same protein
2. isoform 2 has shorter N-ter compare to isoform1
3. 783AA -- 90kDa
1. signal peptide
2. PA - protease-associated domain
2.1 PA -- putative protein recognition domain in distinctive set of TM ubiquitin ligase
2.2 function endocytic pw and cell surface
PA domain of RN43 requires Dishevelled as adaptor to bind with Frizzled receptor --> undergo ubiquitination
3. Transmembrane
4. RING domain which is part of the E3-ubiquitin ligase
Protein domain of RNF43
Location of RNF43:
1. nucleus of human intestinal crypt
2. nucleus of colon cancer cells
3. inner nuclear membrane
4. nuclear periphery
5. nucleoplasm
6. endoplasmic reticulum
7. surface cell membrane
Expression of RNF43 in normal tissues:
** non-neoplasia organs-high level of duodenum, small bowel, colon, and prostate
RNA-seq from 95 human individuals. RPKM -- reads per kilobase of transcript per million mapped (to normalize the expression level of the genes -- make them enable to be compared)
Functions of RNF43;
1.down regulate the wnt signalling by degrading the Frizzled receptor
2. wnt - glycoprotein; function in cell proliferation, migration, cell fate specification, and polarity formation
1. Frizzled of course!
2. lipoprotein receptor-related protein 5/6 (LRP5/6)
all are related to wnt/b-catenin signaling pathway
RNF43 can bind to TCF4 (control the expression level of RNF43) and tight it up to the nuclear membrane.
RNF43 can bind to NEDD-4-like ubiquitin-protein ligase-1 (NEDL1 - E3 ubiquitin ligase) - regulate the p53-mediated transcription.
RNF43 can interact with p53 and suppress transcription activity of p53.
RNF43 binds to HAP95 (chromatin-associated protein interacting the nuclear envelope).
Functions of RNF43 in cancer;
Activation of wnt/b-catenin signaling pw -- cause RNF43 expression -- feed back loop to wnt-receptor degradation --> inactivate the wnt/b-catening pw.
Two possible mechanisms of how RNF43 could be related to the cancer;
1. RNF43 mutation -- lack of degradation of Fz receptor
2. RNF43 mutation caused the release of TCF4 --> the level of TCF4 is related to the carcinogenesis in some cancers
RNF43 and Cancer (focus on role as tumor suppresor)
1. serrated colorectal lesion
2. gastric adenocarcinomas
3. pancreatic cystic lesion and adenocarcinoma
4. ovarian mucinous type
5. endometrial adenocarcinomas
6. cholangiocarcinoma-liver fluke related
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