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FLASH GENE
Symbol GRN contributors: mct - updated : 27-02-2015
HGNC name granulin
HGNC id 4601
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • seven and a half granulin domains composed of 12 cysteine-rich tandem repeat motifs
  • conjugated GlycoP
    isoforms Precursor a 17 aa signal peptide (1.8kda), smaller cleavage products named granulin A, granulin B, granulin C, etc.
    HOMOLOGY
    interspecies homolog to rattus Grn (76pc)
    homolog to murine Grn (75.7pc)
    Homologene
    FAMILY
  • granulin family
  • CATEGORY immunity/defense , transcription factor , protooncogene , signaling cytokine
    SUBCELLULAR LOCALIZATION extracellular
    intracellular,cytoplasm,organelle,mitochondria
    text in pachytene spermatocytes and is found later in the acrosomes of developing spermatids and sperm
    basic FUNCTION
  • having growth modulatory activity
  • having possible cytokine-like activity
  • may play a role in inflammation, wound repair,
  • and tissue remodeling (being a crucial mediator of wound response and tissue repair)
  • involved in the stimulation of chondrocyte proliferation (stimulation mediated by COMP)
  • may act as a wound-healing factor, although the granulins and the full-length PGRN may have opposite functions in wound repair and inflammation
  • germ cell-specific glycoprotein that was expressed meiotically and post-meiotically, having growth-modulating properties
  • importance of progranulin as neuroprotective growth factor
  • important role in tooth formation during postnatal development
  • function for progranulin in modulating the kinetics of programmed cell death that may be relevant for neuron loss in neurodegenerative diseases
  • neurotrophic factor that enhances neuronal survival and axonal growth
  • GRN growth factor, JUNB, and MYOD1 transcription factor form a regulatory loop and act in concert in the course of myogenesis
  • hepatic oncofetal protein regulating ES cell-related signaling molecules
  • key adipokine that mediates HFD (high fat diet)-induced insulin resistance and obesity through production of IL6 in adipose tissue
  • microglial PGRN appears to function as an endogenous modulator of innate immune responses
  • widely expressed secreted protein that is linked to inflammation
  • critical role of GRN in lysosomes
  • is a secretory lysosomal protein that regulates lysosomal function and biogenesis by controlling the acidification of lysosomes
  • role of GRN insufficiency in the pathogenesis of neurodegenerative diseases
  • is likely essential for proper lysosomal function
  • CELLULAR PROCESS cell life, proliferation/growth
    nucleotide, transcription
    PHYSIOLOGICAL PROCESS inflammation , nervous system , reproduction/sex
    text epithelial homeostasis, reproductive, immunological, neuronal function
    PATHWAY
    metabolism
    signaling signal transduction
    cell-cell signaling; positive regulation of cell proliferation
    a component
  • disulfide bridged
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • selectively interacts with the epidermal growth factor repeat domain of COMP but not with the other three functional domains of COMP
  • interacting with TARDBP (may be required as a survival factor for vulnerable neurons, which accumulate cytoplasmic TARDBP fragments because of other reasons)
  • important role of PGRN in neurite outgrowth and involvement of GSK3B in mediating PGRN activity
  • substrate of several protein disulfide isomerase family proteins
  • adipokine induced by TNF and dexamethasone
  • MMP12 is a PGRN proteolytic enzyme, and SLPI an inhibitor of MMP12-induced PGRN proteolysis
  • GRN regulates neuronal outgrowth independent of SORT1
  • overexpression of TMEM106B correlates with elevated levels of GRN, possibly by attenuating lysosomal degradation of GRN
  • ADAM15 participates likely in fertilization through a physical interaction with GRN
  • RETN and GRN represent novel and putative regulators of the fat-brain axis by their ability to cross the blood-brain barrier (BBB) under physiological and pathophysiological condition
  • direct interaction between GRN and CTSD, and a combined reduction of GRN and CTSD synergistically reduced axonal outgrowth
  • role of GRN in PSAP lysosomal trafficking, suggesting that impaired lysosomal trafficking of PSAP is an underlying disease mechanism for NCL and FTLD due to GRN mutations
  • GRN and PSAP facilitate each other lysosomal trafficking and interaction between GRN and PSAP is mediated by granulins and the linker region between saposin B and C
  • cell & other
    REGULATION
    Other SORT1 regulates the levels of brain progranulin (PGRN)
    ASSOCIATED DISORDERS
    corresponding disease(s) FTDU17 , CLN11
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    in corticoadrenal carcinoma (malignant progression)
    constitutional somatic mutation      
    mutations creating null alleles cause tau-negative frontotemporal dementia
    tumoral     --over  
    in uterine leiomyosarcoma
    constitutional   deletion    
    sufficient to cause neurodegeneration
    constitutional   deletion    
    deleted with RUNDC3A in frontotemporal dementia
    constitutional       loss of function
    leads to dysregulated microglial activation and thereby contributes to increased neuron loss with injury
    tumoral     --over  
    in hepatocellular carcinoma but not in the adjacent non-tumor
    constitutional     --low  
    in 65 p100 of children with autism
    constitutional     --over  
    increased GRN in the skin of amyotrophic lateral sclerosis, related to the disease process and metabolic alteration of GRN may take place in the skin of patients with ALS
    constitutional     --over  
    in Alzheimer disease brains, whereas TMEM106B mRNA levels were decreased
    constitutional     --low gain of function
    both PSAP reduction and overexpression lead to significantly elevated extracellular GRN levels
    Susceptibility
  • to Alzheimer disease and Parkinson disease
  • to frontotemporal lobar degeneration (FTLD)
  • Variant & Polymorphism other
  • mutation frequency of GRN mutation was 6.6p100 in FTLD
  • Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    obesity  
    may be a promising therapeutic target for obesity
    osteoarticular  
    potential target for developing and optimizing the therapeutic application in cartilage repair and arthritic disorders
    cancerdigestiveliver
    potential therapeutic target for HCC
    neurologyneurodegenerative 
    therapeutic target for neurodegenerative diseases including motor neuron disease
    immunologyautoimmunearticular
    promising therapeutic target for rheumatoid arthritis
    ANIMAL & CELL MODELS