Granulin

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GRN
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases GRN, CLN11, GEP, GP88, PCDGF, PEPI, PGranulin
External IDs MGI: 95832 HomoloGene: 1577 GeneCards: GRN
RNA expression pattern
PBB GE GRN 211284 s at fs.png

PBB GE GRN 200678 x at fs.png

PBB GE GRN 216041 x at fs.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001012479
NM_002087

NM_008175

RefSeq (protein)

NP_002078

n/a

Location (UCSC) Chr 17: 44.35 – 44.35 Mb Chr 11: 102.43 – 102.44 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/Edit Mouse
Granulin
PDB 1g26 EBI.jpg
the solution structure of a well-folded peptide based on the 31-residue amino-terminal subdomain of human granulin a
Identifiers
Symbol Granulin
Pfam PF00396
InterPro IPR000118
PROSITE PDOC00634
SCOP 1pcn
SUPERFAMILY 1pcn

Granulin is a protein that in humans is encoded by the GRN gene.[3][4][5]

Structure[edit]

Granulins are a family of secreted, glycosylated peptides that are cleaved from a single precursor protein with 7.5 repeats of a highly conserved 12-cysteine granulin/epithelin motif. The 88 kDa precursor protein, progranulin, is also called proepithelin and prostate cancer (PC) cell-derived growth factor. Cleavage of the signal peptide produces mature granulin which can be further cleaved into a variety of active, 6 kDa peptides. These smaller cleavage products are named granulin A, granulin B, granulin C, etc. Epithelins 1 and 2 are synonymous with granulins A and B, respectively.

Function[edit]

Both the peptides and intact granulin protein regulate cell growth. However, different members of the granulin protein family may act as inhibitors, stimulators, or have dual actions on cell growth. Granulin family members are important in normal development, wound healing, and tumorigenesis.[5]

Clinical significance[edit]

The human liver fluke (Opisthorchis viverrini) contributes to the development of bile duct (liver) cancer by secreting a granulin-like growth hormone.[6]

Mutations in the GRN gene have been implicated in up to 25% of frontotemporal lobar degeneration, inherited in an autosomal dominant fashion with high penetrance.[7] Several loss-of-function mutations disease-causing mutations in GRN have been identified.[8][9]

Granulin release by macrophages has been associated with fibrotic hepatic metastasis in pancreatic cancer.[10]

Interactions[edit]

Granulin has been shown to interact with Cyclin T1[11] and TRIB3.[12]

References[edit]

  1. ^ "Human PubMed Reference:". 
  2. ^ "Mouse PubMed Reference:". 
  3. ^ Bhandari V, Bateman A (Nov 1992). "Structure and chromosomal location of the human granulin gene". Biochem Biophys Res Commun. 188 (1): 57–63. doi:10.1016/0006-291X(92)92349-3. PMID 1417868. 
  4. ^ Zhang H, Serrero G (Dec 1998). "Inhibition of tumorigenicity of the teratoma PC cell line by transfection with antisense cDNA for PC cell-derived growth factor (PCDGF, epithelin/granulin precursor)". Proc Natl Acad Sci U S A. 95 (24): 14202–7. Bibcode:1998PNAS...9514202Z. doi:10.1073/pnas.95.24.14202. PMC 24351Freely accessible. PMID 9826678. 
  5. ^ a b "Entrez Gene: GRN granulin". 
  6. ^ Smout MJ, Laha T, Mulvenna J, Sripa B, Suttiprapa S, Jones A, Brindley PJ, Loukas A (October 2009). "A granulin-like growth factor secreted by the carcinogenic liver fluke, Opisthorchis viverrini, promotes proliferation of host cells". PLoS Pathog. 5 (10): e1000611. doi:10.1371/journal.ppat.1000611. PMC 2749447Freely accessible. PMID 19816559. 
  7. ^ Mackenzie IR (2007). "The neuropathology and clinical phenotype of FTD with progranulin mutations". Acta Neuropathologica. 114 (1): 49–40. doi:10.1007/s00401-007-0223-8. PMID 17458552. 
  8. ^ Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, Snowden J, Adamson J, Sadovnick AD, Rollinson S, Cannon A, Dwosh E, Neary D, Melquist S, Richardson A, Dickson D, Berger Z, Eriksen J, Robinson T, Zehr C, Dickey CA, Crook R, McGowan E, Mann D, Boeve B, Feldman H, Hutton M (2006). "Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17". Nature. 442 (7105): 916–919. Bibcode:2006Natur.442..916B. doi:10.1038/nature05016. PMID 16862116. 
  9. ^ Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D, Rademakers R, Vandenberghe R, Dermaut B, Martin JJ, van Duijn C, Peeters K, Sciot R, Santens P, De Pooter T, Mattheijssens M, Van den Broeck M, Cuijt I, Vennekens K, De Deyn PP, Kumar-Singh S, Van Broeckhoven C (2006). "Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21". Nature. 442 (7105): 920–924. Bibcode:2006Natur.442..920C. doi:10.1038/nature05017. PMID 16862115. 
  10. ^ Nielsen, Sebastian R.; Quaranta, Valeria; Linford, Andrea; Emeagi, Perpetua; Rainer, Carolyn; Santos, Almudena; Ireland, Lucy; Sakai, Takao; Sakai, Keiko; Kim, Yong-Sam; Engle, Dannielle; Campbell, Fiona; Palmer, Daniel; Ko, Jeong Heon; Tuveson, David A.; Hirsch, Emilio; Mielgo, Ainhoa; Schmid, Michael C. (18 April 2016). "Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis". Nature Cell Biology. 18 (5): 549–560. doi:10.1038/ncb3340. 
  11. ^ Hoque M, Young TM, Lee CG, Serrero G, Mathews MB, Pe'ery T (March 2003). "The growth factor granulin interacts with cyclin T1 and modulates P-TEFb-dependent transcription". Mol. Cell. Biol. 23 (5): 1688–702. doi:10.1128/MCB.23.5.1688-1702.2003. PMC 151712Freely accessible. PMID 12588988. 
  12. ^ Zhou Y, Li L, Liu Q, Xing G, Kuai X, Sun J, Yin X, Wang J, Zhang L, He F (May 2008). "E3 ubiquitin ligase SIAH1 mediates ubiquitination and degradation of TRB3". Cell. Signal. 20 (5): 942–8. doi:10.1016/j.cellsig.2008.01.010. PMID 18276110. 

Further reading[edit]

External links[edit]