GRN_RAT
ID GRN_RAT Reviewed; 588 AA.
AC P23785;
DT 01-NOV-1991, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-1992, sequence version 3.
DT 25-MAY-2022, entry version 138.
DE RecName: Full=Progranulin {ECO:0000250|UniProtKB:P28799};
DE Short=PGRN {ECO:0000250|UniProtKB:P28799};
DE AltName: Full=Acrogranin {ECO:0000250|UniProtKB:P28798};
DE AltName: Full=Epithelin precursor {ECO:0000303|PubMed:1618805};
DE AltName: Full=Granulin precursor {ECO:0000303|PubMed:8243292};
DE AltName: Full=Proepithelin;
DE Short=PEPI {ECO:0000250|UniProtKB:P28799};
DE Contains:
DE RecName: Full=Paragranulin;
DE Contains:
DE RecName: Full=Granulin-1;
DE AltName: Full=Granulin G;
DE Contains:
DE RecName: Full=Granulin-2;
DE AltName: Full=Granulin F;
DE Contains:
DE RecName: Full=Granulin-3;
DE AltName: Full=Epithelin-2 {ECO:0000303|PubMed:2236009};
DE AltName: Full=Granulin B;
DE Contains:
DE RecName: Full=Granulin-4;
DE AltName: Full=Epithelin-1 {ECO:0000303|PubMed:2236009};
DE AltName: Full=Granulin A;
DE Contains:
DE RecName: Full=Granulin-5;
DE AltName: Full=Granulin C;
DE Contains:
DE RecName: Full=Granulin-6;
DE AltName: Full=Granulin D;
DE Contains:
DE RecName: Full=Granulin-7;
DE AltName: Full=Granulin E;
DE Flags: Precursor;
GN Name=Grn;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Kidney;
RX PubMed=8243292; DOI=10.1210/endo.133.6.8243292;
RA Bhandari V., Giaid A., Bateman A.;
RT "The complementary deoxyribonucleic acid sequence, tissue distribution, and
RT cellular localization of the rat granulin precursor.";
RL Endocrinology 133:2682-2689(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PROTEIN SEQUENCE OF 204-259 AND 278-334.
RC TISSUE=Kidney;
RX PubMed=1618805; DOI=10.1016/s0021-9258(18)42382-4;
RA Plowman G.D., Green J.M., Neubauer M.G., Buckley S.D., McDonald V.L.,
RA Todaro G.J., Shoyab M.;
RT "The epithelin precursor encodes two proteins with opposing activities on
RT epithelial cell growth.";
RL J. Biol. Chem. 267:13073-13078(1992).
RN [3]
RP PROTEIN SEQUENCE OF 204-225 AND 279-299.
RX PubMed=2236009; DOI=10.1073/pnas.87.20.7912;
RA Shoyab M., McDonald V.L., Byles C., Todaro G.J., Plowman G.D.;
RT "Epithelins 1 and 2: isolation and characterization of two cysteine-rich
RT growth-modulating proteins.";
RL Proc. Natl. Acad. Sci. U.S.A. 87:7912-7916(1990).
RN [4]
RP PROTEIN SEQUENCE OF 278-328.
RC TISSUE=Bone marrow;
RX PubMed=2268320; DOI=10.1016/s0006-291x(05)80908-8;
RA Bateman A., Belcourt D.R., Bennett H.P., Lazure C., Solomon S.;
RT "Granulins, a novel class of peptide from leukocytes.";
RL Biochem. Biophys. Res. Commun. 173:1161-1168(1990).
CC -!- FUNCTION: Secreted protein that acts as a key regulator of lysosomal
CC function and as a growth factor involved in inflammation, wound healing
CC and cell proliferation (By similarity). Regulates protein trafficking
CC to lysosomes and, also the activity of lysosomal enzymes (By
CC similarity). Facilitates also the acidification of lysosomes, causing
CC degradation of mature CTSD by CTSB (By similarity). In addition,
CC functions as wound-related growth factor that acts directly on dermal
CC fibroblasts and endothelial cells to promote division, migration and
CC the formation of capillary-like tubule structures (By similarity). Also
CC promotes epithelial cell proliferation by blocking TNF-mediated
CC neutrophil activation preventing release of oxidants and proteases (By
CC similarity). Moreover, modulates inflammation in neurons by preserving
CC neurons survival, axonal outgrowth and neuronal integrity (By
CC similarity). {ECO:0000250|UniProtKB:P28798,
CC ECO:0000250|UniProtKB:P28799}.
CC -!- FUNCTION: [Granulin-3]: Inhibits epithelial cell proliferation and
CC induces epithelial cells to secrete IL-8.
CC {ECO:0000250|UniProtKB:P28799}.
CC -!- FUNCTION: [Granulin-7]: Stabilizes CTSD through interaction with CTSD
CC leading to maintain its aspartic-type peptidase activity.
CC {ECO:0000250|UniProtKB:P28799}.
CC -!- SUBUNIT: Progranulin is secreted as a homodimer. Interacts with SLPI;
CC interaction protects progranulin from proteolysis. Interacts (via
CC region corresponding to granulin-7 peptide) with CTSD; stabilizes CTSD
CC and increases its proteolytic activity. Interacts (via region
CC corresponding to granulin-7 peptide) with SORT1; this interaction
CC mediates endocytosis and lysosome delivery of progranulin; interaction
CC occurs at the neuronal cell surface in a stressed nervous system.
CC Interacts with PSAP; facilitates lysosomal delivery of progranulin from
CC the extracellular space and the biosynthetic pathway. Forms a complex
CC with PSAP and M6PR; PSAP bridges the binding between progranulin and
CC M6PR. Forms a complex with PSAP and SORT1; progranulin bridges the
CC interaction between PSAP and SORT1; facilitates lysosomal targeting of
CC PSAP via SORT1; interaction enhances PSAP uptake in primary cortical
CC neurons. Interacts (via regions corresponding to granulin-2 and
CC granulin-7 peptides) with GBA; this interaction prevents aggregation of
CC GBA-SCARB2 complex via interaction with HSPA1A upon stress. Interacts
CC (via region corresponding to granulin-7 peptide) with HSPA1A; mediates
CC recruitment of HSPA1A to GBA and prevents GBA aggregation in response
CC to stress. {ECO:0000250|UniProtKB:P28799}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:P28799}. Lysosome
CC {ECO:0000250|UniProtKB:P28799}. Note=Endocytosed by SORT1 and delivred
CC to lysosomes. Targeted to lysosome by PSAP via M6PR and LRP1, in both
CC biosynthetic and endocytic pathways (By similarity). Co-localized with
CC GBA in the intracellular trafficking compartments until to lysosome (By
CC similarity). {ECO:0000250|UniProtKB:P28798,
CC ECO:0000250|UniProtKB:P28799}.
CC -!- TISSUE SPECIFICITY: Ubiquitous; most abundant in the spleen and several
CC tissues of endocrine significance. {ECO:0000269|PubMed:8243292}.
CC -!- PTM: Cleaved by ELANE; proteolysis is blocked by SLPI and is
CC concentration- and time-dependent and induces CXCL8/IL-8 production;
CC granulin-3 and granulin-4 are resistant to ELANE. Cleaved by CTSL in
CC lysosome thus regulating the maturation and turnover of progranulin
CC within the lysosome. {ECO:0000250|UniProtKB:P28799}.
CC -!- SIMILARITY: Belongs to the granulin family. {ECO:0000305}.
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DR EMBL; M97750; AAA16903.1; -; mRNA.
DR EMBL; X62322; CAA44198.1; -; mRNA.
DR PIR; B38128; B38128.
DR RefSeq; NP_058809.2; NM_017113.2.
DR AlphaFoldDB; P23785; -.
DR SMR; P23785; -.
DR BioGRID; 247826; 4.
DR IntAct; P23785; 2.
DR STRING; 10116.ENSRNOP00000028557; -.
DR GlyGen; P23785; 3 sites.
DR jPOST; P23785; -.
DR PaxDb; P23785; -.
DR PRIDE; P23785; -.
DR GeneID; 29143; -.
DR KEGG; rno:29143; -.
DR UCSC; RGD:61983; rat.
DR CTD; 2896; -.
DR RGD; 61983; Grn.
DR eggNOG; KOG4296; Eukaryota.
DR InParanoid; P23785; -.
DR OrthoDB; 162721at2759; -.
DR PhylomeDB; P23785; -.
DR Reactome; R-RNO-6798695; Neutrophil degranulation.
DR PRO; PR:P23785; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB.
DR GO; GO:0005576; C:extracellular region; ISS:UniProtKB.
DR GO; GO:0005615; C:extracellular space; ISO:RGD.
DR GO; GO:0005794; C:Golgi apparatus; ISS:UniProtKB.
DR GO; GO:0005770; C:late endosome; ISS:UniProtKB.
DR GO; GO:0005765; C:lysosomal membrane; ISS:UniProtKB.
DR GO; GO:0005764; C:lysosome; ISS:UniProtKB.
DR GO; GO:0016020; C:membrane; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0098793; C:presynapse; IEA:GOC.
DR GO; GO:0005802; C:trans-Golgi network; ISS:UniProtKB.
DR GO; GO:0031982; C:vesicle; ISS:UniProtKB.
DR GO; GO:0051087; F:chaperone binding; ISS:UniProtKB.
DR GO; GO:0005125; F:cytokine activity; IEA:UniProtKB-KW.
DR GO; GO:0002265; P:astrocyte activation involved in immune response; ISS:UniProtKB.
DR GO; GO:0001835; P:blastocyst hatching; ISO:RGD.
DR GO; GO:0035988; P:chondrocyte proliferation; IMP:RGD.
DR GO; GO:0007566; P:embryo implantation; ISO:RGD.
DR GO; GO:0035641; P:locomotory exploration behavior; ISO:RGD.
DR GO; GO:0007042; P:lysosomal lumen acidification; ISS:UniProtKB.
DR GO; GO:1905146; P:lysosomal protein catabolic process; ISO:RGD.
DR GO; GO:0007041; P:lysosomal transport; ISS:UniProtKB.
DR GO; GO:0007040; P:lysosome organization; ISS:UniProtKB.
DR GO; GO:0060179; P:male mating behavior; IMP:RGD.
DR GO; GO:0002282; P:microglial cell activation involved in immune response; ISS:UniProtKB.
DR GO; GO:0051346; P:negative regulation of hydrolase activity; ISO:RGD.
DR GO; GO:0050728; P:negative regulation of inflammatory response; ISS:UniProtKB.
DR GO; GO:0045824; P:negative regulation of innate immune response; ISS:UniProtKB.
DR GO; GO:1903979; P:negative regulation of microglial cell activation; ISS:UniProtKB.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; ISS:UniProtKB.
DR GO; GO:1902564; P:negative regulation of neutrophil activation; ISS:UniProtKB.
DR GO; GO:0060266; P:negative regulation of respiratory burst involved in inflammatory response; ISS:UniProtKB.
DR GO; GO:0061351; P:neural precursor cell proliferation; IMP:RGD.
DR GO; GO:0045766; P:positive regulation of angiogenesis; ISS:UniProtKB.
DR GO; GO:1905247; P:positive regulation of aspartic-type peptidase activity; ISS:UniProtKB.
DR GO; GO:0048680; P:positive regulation of axon regeneration; ISS:UniProtKB.
DR GO; GO:0030335; P:positive regulation of cell migration; ISO:RGD.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; ISS:UniProtKB.
DR GO; GO:1900426; P:positive regulation of defense response to bacterium; ISS:UniProtKB.
DR GO; GO:0060999; P:positive regulation of dendritic spine development; IMP:RGD.
DR GO; GO:0010595; P:positive regulation of endothelial cell migration; ISS:UniProtKB.
DR GO; GO:0050679; P:positive regulation of epithelial cell proliferation; ISS:UniProtKB.
DR GO; GO:0106016; P:positive regulation of inflammatory response to wounding; ISS:UniProtKB.
DR GO; GO:1905673; P:positive regulation of lysosome organization; ISS:UniProtKB.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; ISS:UniProtKB.
DR GO; GO:0010976; P:positive regulation of neuron projection development; IMP:RGD.
DR GO; GO:1903334; P:positive regulation of protein folding; ISS:UniProtKB.
DR GO; GO:0050821; P:protein stabilization; ISS:UniProtKB.
DR GO; GO:0050727; P:regulation of inflammatory response; IBA:GO_Central.
DR GO; GO:1905671; P:regulation of lysosome organization; ISO:RGD.
DR GO; GO:0032355; P:response to estradiol; IDA:RGD.
DR GO; GO:0060041; P:retina development in camera-type eye; ISO:RGD.
DR GO; GO:0048488; P:synaptic vesicle endocytosis; IMP:RGD.
DR Gene3D; 2.10.25.160; -; 7.
DR InterPro; IPR000118; Granulin.
DR InterPro; IPR039036; Granulin_fam.
DR InterPro; IPR037277; Granulin_sf.
DR PANTHER; PTHR12274; PTHR12274; 1.
DR Pfam; PF00396; Granulin; 7.
DR SMART; SM00277; GRAN; 7.
DR PROSITE; PS00799; GRANULINS; 7.
PE 1: Evidence at protein level;
KW Cytokine; Direct protein sequencing; Disulfide bond; Glycoprotein;
KW Lysosome; Reference proteome; Repeat; Secreted; Signal.
FT SIGNAL 1..17
FT /evidence="ECO:0000255"
FT CHAIN 18..588
FT /note="Progranulin"
FT /id="PRO_0000012710"
FT PEPTIDE 18..47
FT /note="Paragranulin"
FT /evidence="ECO:0000250|UniProtKB:P28799"
FT /id="PRO_0000446332"
FT PEPTIDE 58..113
FT /note="Granulin-1"
FT /id="PRO_0000012711"
FT PEPTIDE 122..178
FT /note="Granulin-2"
FT /id="PRO_0000012712"
FT PEPTIDE 204..259
FT /note="Granulin-3"
FT /id="PRO_0000012713"
FT PEPTIDE 278..334
FT /note="Granulin-4"
FT /id="PRO_0000012714"
FT PEPTIDE 361..413
FT /note="Granulin-5"
FT /id="PRO_0000012715"
FT PEPTIDE 438..492
FT /note="Granulin-6"
FT /id="PRO_0000012716"
FT PEPTIDE 512..567
FT /note="Granulin-7"
FT /id="PRO_0000012717"
FT CARBOHYD 38
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 372
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 525
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 125..138
FT /evidence="ECO:0000250|UniProtKB:P28799"
FT DISULFID 132..148
FT /evidence="ECO:0000250|UniProtKB:P28799"
FT DISULFID 281..293
FT /evidence="ECO:0000250|UniProtKB:P28799"
FT DISULFID 287..303
FT /evidence="ECO:0000250|UniProtKB:P28799"
FT DISULFID 294..311
FT /evidence="ECO:0000250|UniProtKB:P28799"
FT DISULFID 304..318
FT /evidence="ECO:0000250|UniProtKB:P28799"
FT DISULFID 312..325
FT /evidence="ECO:0000250|UniProtKB:P28799"
FT DISULFID 319..332
FT /evidence="ECO:0000250|UniProtKB:P28799"
FT DISULFID 363..375
FT /evidence="ECO:0000250|UniProtKB:P28799"
FT DISULFID 369..385
FT /evidence="ECO:0000250|UniProtKB:P28799"
FT DISULFID 394..407
FT /evidence="ECO:0000250|UniProtKB:P28799"
FT DISULFID 401..413
FT /evidence="ECO:0000250|UniProtKB:P28799"
FT CONFLICT 201
FT /note="S -> FP (in Ref. 2; CAA44198)"
FT /evidence="ECO:0000305"
FT CONFLICT 307..308
FT /note="TK -> SB (in Ref. 4; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 324
FT /note="Q -> T (in Ref. 4; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 388
FT /note="M -> I (in Ref. 2; CAA44198)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 588 AA; 63370 MW; 113D434F7E099B31 CRC64;
MWILVSWLAL VARLVAGTQC PDGQFCPVAC CLDQGGANYS CCNPLLDTWP IITSRRLDGS
CQIRDHCPDG YSCLLTVSGT SSCCPFSEGV SCDDGQHCCP RGFHCSADGK SCSQISDSLL
GAVQCPGSQF ECPDSATCCI MIDGSWGCCP MPQASCCEDR VHCCPHGASC DLVHTRCISP
TGTHPLLKKF PAQRTNRAVA SFSVVCPDAK TQCPDDSTCC ELPTGKYGCC PMPNAICCSD
HLHCCPQDTV CDLIQSKCIS KDYTTDLMTK LPGYPVNEVK CDLEVSCPDG YTCCRLNTGA
WGCCPFTKAV CCEDHIHCCP AGFQCHTETG TCELGVLQVP WMKKVTASLS LPDPQILKND
VPCDDFSSCP SNNTCCRLSS GDWGCCPMPE AVCCLDHQHC CPQGFKCMDE GYCQKGDRMV
AGLEKMPVRQ TTLLQHGDIG CDQHTSCPVG QTCCPSLKGS WACCQLPHAV CCEDRQHCCP
AGYTCNVKAR TCEKDAGSVQ PSMDLTFGSK VGNVECGAGH FCHDNQSCCK DSQGGWACCP
YVKGVCCRDG RHCCPIGFHC SAKGTKCLRK KTPRWDILLR DPAPRPLL
