GP,78, RNF45 (Kr.16q13), AMFR, E3 ubikitiiniligaasi (osallistuu lipidimetabolian säätelyyn)

 Tämä GP78 proteiini kuuluu  ERAD mekanismiin Endoplasmisessa koneistossa ja sen normaali tehtävä on  säätää kolesterolitietä ja sterolituotteiden vaikutuksesta  se lähettää  HMG-CoA reduktaasin proteosomisilppuriin.    Toimiiko se ? Entä jos se ei ole normaali?  Tämä geeni löydettiin ensin AMFR nimisenä autokriinisenä motiliteettifaktorina, tuumorimotiliteettia stimuloivana tekijänä  tuumorislujen eritetuotteista.   tätä funktiota  kyllä  korvaa statiinilääkket, jotka  blokeeraavat HMGCoA reduktaasin , muta samalla kyllä säätävät tämän entsyymin erityksen ylös, mikä voi olla haitallista, koska  tarvitaan  korkeampia lääkeannoksia.  Dieettitietä voidaan vaikuttaa  sterolimääriin ja laatuihin ja se voi olla  kaikkein  fysiologisin tie vaikuttaa, kun  tässä tieto lisääntyy.  Normaalisti eläimillä tämä  GP78   näyttää toimivan, harva eläin lihoo luonnon ravinnolla , tosin niiden tuumoritilanteesta kuka tietää eikä eläinten elinikäkään ole kovin . Tästä linkistä saa selittävän kuvan: kehuttava.
https://www.sciencedirect.com/science/article/pii/S1097276505015273#fig6

OubMed Geenitieto
https://www.ncbi.nlm.nih.gov/gene/267

AMFR autocrine motility factor receptor [ Homo sapiens (human) ]

Gene ID: 267, updated on 22-May-2018

Also known as GP78, RNF45

Summary

This locus encodes a glycosylated transmembrane receptor. Its ligand, autocrine motility factor, is a tumor motility-stimulating protein secreted by tumor cells. The encoded receptor is also a member of the E3 ubiquitin ligase family of proteins. It catalyzes ubiquitination and endoplasmic reticulum-associated degradation (ERAD)  of specific proteins. [provided by RefSeq, Feb 2012]

Expression

Ubiquitous expression in testis (RPKM 45.4), kidney (RPKM 36.4) and 25 other tissues See more

Related articles in PubMed

1. Autocrine motility factor receptor promotes the proliferation of human acute monocytic leukemia THP-1 cells. Wang Y, et al. Int J Mol Med, 2015 Sep. PMID 26136223, Free PMC Article
2. Affinity proteomics discovers decreased levels of AMFR in plasma from Osteoporosis patients. Qundos U, et al. Proteomics Clin Appl, 2016 Jun. PMID 25689831, Free PMC Article
3. Aberrant expression of the autocrine motility factor receptor correlates with poor prognosis and promotes metastasis in gastric carcinoma. Huang Z, et al. Asian Pac J Cancer Prev, 2014. PMID 24568530
4. gp78 is specifically expressed in human prostate cancer rather than normal prostate tissue. Shang Y, et al. J Mol Histol, 2013 Dec. PMID 23666464
5. gp78: a multifaceted ubiquitin ligase that integrates a unique protein degradation pathway from the endoplasmic reticulum. Chen Z, et al. Curr Protein Pept Sci, 2012 Aug. PMID 22812524

See all (117) citations in PubMed

GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

1. This is the first study to show that HSPA1L mediated HIF-1alpha stabilization. In addition, this is the first study to show that GP78 inactivation promotes cancer cell proliferation, migration and eventual tumor growth both in vivo and in vitro by increasing cellular prion protein.
2. overexpression of gp78 or SVIP suppression may eliminate the toxic gain of function associated with polymerization of ZAAT, thus providing a potential new therapeutic approach to the treatment of alpha-1 antitrypsin deficiency
3. Despite its interaction with gp78, Lnp does not seem to have a broad function in degradation of misfolded ER proteins.
4. Further study discovered that the gp78 CUE domain works as a proofreading machine during the growth of K48-linked polyubiquitin chains to ensure the linkage specificity. Together, our studies uncover a novel mechanism underlying the linkage specificity determination of longer polyubiquitin chains.
5. AMFR expression is significantly reduced in plasma from osteoporosis patients.
6. Catalytic inactivation of MGRN1 results in elevated levels of GP78 and a consequential increase in the initiation of mitophagy.
7. Authors conclude that the Hrd1 complex forms an essential retrotranslocation module that is evolutionarily conserved, but the mammalian ERAD system uses additional ubiquitin ligases to assist Hrd1 during retrotranslocation.
8. Downregulation of AMFR induced cell cycle arrest at the G0/G1 phase, and increased apoptosis of the THP1 cells.
9. The authors identify USP13 as a gp78-associated deubiquitinase that eliminates ubiquitin conjugates from Ubl4A to maintain the functionality of Bag6.
10. Data show that autocrine motility factor receptor (AMFR) and NOTCH1 protein are the direct target genes of microRNA miR-139-5p in colorectal cancer (CRC)

Lisätietoa 2018 RNF45  (RNF Zn Finger proteiinista)  GP78 E3 ubikitiiniligaasista.

 https://www.ncbi.nlm.nih.gov/pubmed/12670940

J Biol Chem. 2003 Jun 27;278(26):23984-8. Epub 2003 Apr 1.

Overexpression of the tumor autocrine motility factor receptor Gp78, a ubiquitin protein ligase, results in increased ubiquitinylation and decreased secretion of apolipoprotein B100 in HepG2 cells...  This action of gp78 was specific: overexpression of the protein did not affect secretion of either albumin or apolipoprotein AI. Furthermore, overexpression of a cytosolic E3, Itch, had no effect on apoB secretion. Finally, using an in vitro translation system, we demonstrated that gp78 led to increased ubiquitinylation and proteasomal degradation of apoB48. Together, these results indicate that an ER-associated protein, gp78, is a bona fide E3 ligase in the apoB ER-associated degradation pathway.

• Toinen lisätieto: RNF45 ja RNF145  omaavat saman ubikitinaatio ja hajoituskohteen:   HMC-CoA reduktaasi  ubikitinoidaan hajoitettavaksi  steroli-induktiosta.

RNF 45 (GP78)   oli  aiemmin jo todettu  ubikitiiniligaasiksi,  joka ubikitinoi ja johti silppuriin HMG-CoA-reduktaasin  steroli-induktiosta. Tutkijat etsivät muita ubikitiiniligaaseja,  jotka suorittavat  samaa ja havaitsivat RNF145, josta on vähemmän artikkeleita saatavilla.

 https://www.ncbi.nlm.nih.gov/pubmed/29374057 
To identify other ubiquitin ligase(s) that may function together with gp78 in triggering HMGCR degradation,

J Biol Chem. 2018 Mar 16;293(11):4047-4055. doi: 10.1074/jbc.RA117.001260. Epub 2018 Jan 26. Ring finger protein 145 (RNF145) is a ubiquitin ligase for sterol-induced degradation of HMG-CoA reductase. Jiang LY¹, Jiang W¹, Tian N¹, Xiong YN¹, Liu J¹, Wei J¹, Wu KY¹, Luo J¹, Shi XJ², Song BL³.

Abstract

Cholesterol biosynthesis is tightly regulated in the cell. For example, high sterol concentrations can stimulate degradation of the rate-limiting cholesterol biosynthetic enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase, HMGCR). HMGCR is broken down by the endoplasmic reticulum membrane-associated (ERAD) protein complexes consisting of insulin-induced genes (Insigs) and the E3 ubiquitin ligase gp78. Here we found that HMGCR degradation is partially blunted in Chinese hamster ovary (CHO) cells lacking gp78 (gp78-KO). To identify other ubiquitin ligase(s) that may function together with gp78 in triggering HMGCR degradation, we performed a small-scale short hairpin RNA-based screening targeting endoplasmic reticulum-localized E3s. We found that knockdown of both ring finger protein 145 (Rnf145) and gp78 (Rnf45)  genes abrogates sterol-induced degradation of HMGCR in CHO cells. We also observed that RNF145 interacts with Insig-1 and -2 proteins and ubiquitinates HMGCR. Moreover, the tetrapeptide sequence YLYF in the sterol-sensing domain and the Cys-537 residue in the RING finger domain were essential for RNF145 binding to Insigs and RNF145 E3 activity, respectively. Of note, amino acid substitutions in the YLYF or of Cys-537 completely abolished RNF145-mediated HMGCR degradation. In summary, our study reveals that RNF145, along with gp78 (RNF45) , promotes HMGCR degradation in response to elevated sterol levels and identifies residues essential for RNF145 function.