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FLASH GENE
Symbol MANF contributors: mct/npt/pgu - updated : 04-06-2015
HGNC name mesencephalic astrocyte-derived neurotrophic factor
HGNC id 15461
Location 3p21.1      Physical location : 51.422.691 - 51.426.827
Synonym name
  • arginine rich protein with an imperfect trinucleotide repeat encoding a stretch of arginines
  • arginine-rich, mutated in early stage tumors
  • mesencephalic astrocyte-derived neurotrophic factor
    • Synonym symbol(s) MRC, ARP, ARME, ARMET, MGC142148, MGC142150
    DNA
    TYPE functioning gene
    STRUCTURE 4.07 kb     4 Exon(s)
    text structure an imperfect trinucleotide repeat encoding a stretch of arginines
    MAPPING cloned Y linked   status confirmed
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    4 - 958 20 185 - 2012 2212053
    3 - - - - - 2012 2212053
  • lacking exon 1, and which is presumably not secreted
    		•
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestivesalivary gland     Homo sapiens
    Nervousbrain   highly Homo sapiens
    Reproductivemale systemtestis    Homo sapiens
    Urinarykidney    
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Nervousneuron Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N-terminal domain saposin-like lipid-binding domain
  • C-terminus contains a CKGC disulphide bridge, such as reductases and disulphide isomerases, consistent with a role in ER stress response , protecting neurons intracellularly as efficiently as XRCC6
  • at the extreme C terminus is the sequence RTDL, which resembles the canonical ER retention signal (KDEL), required for binding to the cell surface, and MANF is the only protein in the human proteome known to contain these four C-terminal AAs
    • HOMOLOGY
    Homologene
    FAMILY
  • ARMET family
    • CATEGORY tumor suppressor
    SUBCELLULAR LOCALIZATION extracellular
        plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,organelle,Golgi
    intracellular,nucleus
    text
  • may thus bind lipids or membranes
  • localized in the ER and Golgi and was also a secreted protein
  • endoplasmic reticulum (ER) stress-responsive protein
  • in part, MANF was retained in the SR/ER via its calcium-dependent interaction with the SR/ER-resident protein, HSPA5 (glucose-regulated protein 78 kDa)
  • MANF co-localized with RTN1 in the ER
    • basic FUNCTION
  • may be involved in oncogenesis
  • selectively promotes the survival of dopamine neurons of the ventral midbrain
  • ER stress E-II-dependent gene that likely contributes to quality control of proteins in the ER
  • secreted mediator of the adaptive pathway of unfolded protein response
  • cerebral ischemia-induced MANF expression may be protective to the neurons
  • when expressed intracellularly, MANF can efficiently protect the apoptotic neurons
  • plays an important role in protection of neurodegenerative, apoptotic, and stress conditions, which thereby makes it a highly potential therapeutic agent
  • act as an neurotrophic factor, and is secreted in response to ER stress
  • MANF and CRELD2 are genotype-specific ER stress response proteins with substrate specificities
  • developmentally regulated and may play a role in the maturation of the central nervous system (CNS)
  • MANF and CDNF can protect cells during endoplasmic reticulum (ER) stress
  • is a factor in regulating the secretion of CRELD2 through four C-terminal AAs, RTDL and REDL, and the fluctuation of intracellular MANF seems to potentiate the secretion of CRELD2
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
    RNA putative binding
    small molecule
    protein
  • CRELD2 and MANF, are oppositely regulated by the overexpression of 78&
    • 8201;kDa glucose-regulated protein (HSPA5)
    cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral somatic mutation      
    in renal cell carcinoma
    tumoral somatic mutation      
    squamous cell carcinoma of the head and neck, lung, breast, pancreas and prostate carcinomas
    constitutional     --over  
    in the early stage of cerebral ischemia
    constitutional       gain of function
    by endoplasmic reticulum (ER) stress
    Susceptibility
    Variant & Polymorphism
    Candidate gene
  • specifically promotes beta cell proliferation and survival, thereby constituting a therapeutic candidate for beta cell protection and regeneration
    • Marker
    Therapy target
    SystemTypeDisorderPubmed
    neurologyneurodegenerativeParkinson/dementia Parkinsonism
    selective, neuroprotective effect of MANF for dopaminergic neurons suggests that it may be indicated for the treatment of Parkinson disease
    ANIMAL & CELL MODELS
  • Manf-deficient mice that strikingly develop severe diabetes due to progressive postnatal reduction of beta cell mass, caused by decreased proliferation and increased apoptosis