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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

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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
	System Type Disorder Pubmed neurology neurodegenerative Parkinson/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