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FLASH GENE

Symbol

HSPA9

contributors: mct/ - updated : 21-04-2015

HGNC name	heat shock 70kDa protein 9 (mortalin)
HGNC id	5244

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
STRUCTURE	20.09 kb     17 Exon(s)

MAPPING

cloned

Y

linked

N

status

confirmed

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_004134 17 - 3506 NP_004125 70 679 - 2000 10944461 CRP40 - splicing 1053 40 350 - 2009 19280369 novel catecholamine binding function and this chaperone-like protein may be neuroprotective in dopamine-related central nervous system disorders

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol blood / hematopoietic spleen       highly Digestive esophagus       highly Endocrine adrenal gland       highly Nervous brain       highly Homo sapiens Reproductive female system breast mammary gland   highly Respiratory lung       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Blood / Hematopoietic bone marrow       Connective bone       Muscular striatum skeletal

cells

System Cell Pubmed Species Stage Rna symbol Nervous glia Homo sapiens Nervous neuron Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains

51-AAs N-terminal MTS sequence

HOMOLOGY

interspecies

homolog to murine mortalin 2

intraspecies

homolog to mitochondrial stress-70 protein

Homologene

FAMILY

heat shock protein 70 (HSP70) family

CATEGORY

chaperone/stress , regulatory , transcription factor , protooncogene

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,organelle,mitochondria,matrix
	intracellular,cytoplasm,organelle,endoplasmic reticulum
	intracellular,cytoplasm,cytosolic,vesicle
text	not exclusively in mitochondria but also present in other organelles
	found in multiple subcellular localizations such as the endoplasmic reticulum, cytoplasmic vesicles and the cytosol
	majority of mortalin is located within the mitochondrial matrix (

basic FUNCTION	playing a role in the control of cell proliferation
	implicated in the control of cell proliferation and cellular aging
	controls centrosome duplication via modulating centrosomal localization of TP53
	essential role in the differentiation of neuroblastoma (
	plays a central role in mitochondrial biogenesis through its capacity to direct the import of nuclear-encoded proteins into the mitochondria
	multifunctional protein that is capable of binding the neurotransmitter, dopamine, within the brain
	plays an essential role in the regulation of dopamine-dependent behavior and plays an even greater role in the pathogenesis of schizophrenia
	mitochondrial matrix chaperone, synthesized as a precursor protein which is cleaved into its mature form after import into mitochondria in a mitochondrial membrane potential-dependent manner
	PINK1 and HSPA9 accumulated in different cellular compartments, and these two proteins share, at least partially, the same pathway of mitochondrial import
	functional constituent of intracellular vesicles of a nonclathrin-, noncaveolin-dependent pathway that was sensitive to membrane cholesterol depletion
	role of this mitochondrial chaperone in neurodegeneration and potential impaired mitochondrial protein quality control in Parkinson disease
	plays an important role in the maintenance of mitochondrial homeostasis as critically related to neurodegeneration
	may also act in signaling pathways responsible for mitochondrial stress response and the maintenance of mitochondrial integrity similar to that of the redox-sensing protein PARK7
	crucial involvement of mortalin in the maintenance of mitochondrial morphology due to its function in the mitochondrial matrix
	functions to maintain mitochondrial homeostasis and antagonize oxidative stress injury
	plays an indispensible role in helping native protein refolding and importing proteins into the mitochondrial matrix
	proposed function of HSPA9 and HSCB as the chaperone and co-chaperone, respectively, for human mitochondrial Fe-S cluster biosynthesis
	HSPA9 facilitates BRAF-mutant tumor cell survival by suppressing SLC25A6-mediated mitochondrial membrane permeability

CELLULAR PROCESS	cell life, proliferation/growth
	cell life, senescence
	nucleotide, transcription
	protein, post translation, folding

PHYSIOLOGICAL PROCESS

development

text	control of cell proliferation and cellular aging

PATHWAY

metabolism

signaling

a component	component of the chaperone GRP75/Mortalin/HSPA9B, a mitochondrial stress-induced peptide
	functional constituent of noncaveolar, membrane raft-associated endocytic vesicles
	HSPA9/PARK7 complex guards against mitochondrial oxidative stress and is indispensable for the maintenance of HSCs

INTERACTION

DNA

RNA

small molecule

protein	binding to TRA1
	interacting HSPD1 through its N-terminal region (involvement in tumorigenesis, functional distinction in pathways involved in senescence)
	cytosolic mortalin binds TP53 and by doing so, prevents translocation of the tumor suppressor into the nucleus
	mitochondrial PARK7-interacting protein, also involved in the oxidative stress response
	interacting with DNLZ (conserved histidine is critical for DNLZ regulation of mitochondrial HSPA9 catalytic activity)
	interact with TP53 (both wild and mutant types) and inactivates its transcriptional activation and apoptotic functions in cancer cells
	interacting with PARK2 (relatively decreased mortalin expression level and its impaired interaction with PARK2 could affect its roles in mitochondrial function)
	interacts with fusion- and/or fission-related proteins and affects their mitochondrial location or translocation
	HSPA9 was required for RARA/RXRA-mediated transcriptional regulation and was shown to reduce the proteasome-mediated degradation of RARA/RXRA in a RA-dependent manner
	HSCB interacts with multiple proteins involved in ISC biogenesis including the ISCU ISC biogenesis complex and the HSPA9 ISC chaperone
	binds preferentially to the D-state of ISCU and HSCB binds preferentially to the S-state of ISCU
	activated the ATPase activity of HSPA9, and this activation was greatly increased by the addition of ISCU
	CDKN1A has dual effects under HSPA9-depleted conditions, i.e., mediating cell cycle arrest while limiting cell death
	interaction between BCL2 and BL2L1 with a stress chaperone, mortalin (HSPA9)
	ACSL5-induced mitochondrial HSPA9 expression is assumed to be a stress response to ACSL5-related changes in lipid metabolism and is regulated by the TP53 status
	SLC25A6 is a previously unknown HSPA9 substrate and cell survival/death effector

cell & other

REGULATION

activated by

HSCB

Other

differentially regulated in response to dopaminergic modulation

ASSOCIATED DISORDERS

corresponding disease(s)

related resource

MITOP database

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --over   contributes significantly to tumorigenesis in breast carcinoma tumoral     --over   correlated with malignant transformation and poor cancer prognosis ( constitutional     --low   in the mitochondrial fraction of neurons from the substantia nigra of Parkinson disease patients constitutional     --low   of HSPA8 and HSPA9 was observed in Alzheimer disease across the three brain regions compared to the controls, suggesting their participation in AD pathogenesis

Susceptibility

to Parkinson disease (PD)

Variant & Polymorphism other	putative mutations in the mortalin, although rare, could contribute to the risk of developing PD

Candidate gene
Marker
Therapy target	a good candidate target for cancer therapy
	System Type Disorder Pubmed cancer hemopathy   novel target for cancer adjuvant immunotherapy cancer digestive liver targeting HSPA9-TP53 interaction with either HSPA9 small hairpin RNA or a chemical or peptide inhibitor could induce p53-mediated tumor cell-specific apoptosis in hepatocellular carcinoma tumor     targeting HSPA9 has potential as a selective therapeutic strategy in B-Raf-mutant or MEK-ERK-driven tumors

ANIMAL & CELL MODELS