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FLASH GENE

Symbol

PRKAA1

contributors: mct - updated : 07-06-2016

HGNC name	protein kinase, AMP-activated, alpha 1 catalytic subunit
HGNC id	9376

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Location	5p13.1      Physical location : 40.759.481 - 40.798.297
Synonym name	AMPK, alpha-1 chain
	5'-AMP-activated protein kinase, catalytic alpha-1 chain
Synonym symbol(s)	AMPKA1, AMPK, AMPK1, MGC33776, MGC57364
EC.number	2.7.11.1/2.7.11.26/2.7.11.27

DNA

TYPE	functioning gene
STRUCTURE	38.82 kb     10 Exon(s)

10 Kb 5' upstream gene genomic sequence study

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_006251 9 - 5085 NP_006242 64 559 - 1996 9224708 NM_206907 10 - 5130 NP_996790 65.4 574 - -

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 Cardiovascular vessel       moderately Digestive esophagus       moderately   mouth tongue     moderately Endocrine parathyroid       highly Hearing/Equilibrium ear       moderately Nervous nerve       moderately Reproductive male system testis     moderately Respiratory respiratory tract larynx     moderately   respiratory tract trachea     predominantly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective adipose     moderately

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains

conjugated

PhosphoP

mono polymer

heteromer , trimer

HOMOLOGY

interspecies	ortholog to rattus Prkaa1 (99.1pc)
	ortholog to murine Prkaa1 (98.7pc)

Homologene

FAMILY	protein kinase superfamily
	Ser/Thr protein kinase family
	SNF1 subfamily

CATEGORY

enzyme , regulatory

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,cytosolic
	intracellular,nucleus,nucleoplasm

basic FUNCTION	responsible for the regulation of fatty acid synthesis by phosphorylation of acetyl-CoA carboxylase
	regulating cholesterol synthesis via phosphorylation and inactivation of hormone-sensitive lipase and hydroxymethylglutaryl-CoA reductase
	energy-sensing enzyme believed to be a critical regulator of glucose and fat metabolism in skeletal muscle during exercise
	appearing to act as a metabolic stress-sensing protein kinase switching off biosynthetic pathways when cellular ATP levels are depleted and when 5'-AMP rises in response to fuel limitation and/or hypoxia
	heterotrimeric protein complex that responds to the cellular energy status by switching off ATP-consuming pathways and switching on ATP-generating pathways when ATP is limiting
	acting as a cAMP-dependent protein kinase
	acting as an eukaryotic elongation factor-2 kinase activator
	involved in the activation of MAPK
	had no role in oxidative stress-induced breakdown of RPE barrier function
	involved in the pathogenesis of Alzheimer disease
	critical roles in regulating growth and reprogramming metabolism, and has recently been connected to cellular processes such as autophagy and cell polarity
	in addition to its function in ATP homeostasis, has a key function in NADPH maintenance, which is critical for cancer cell survival under energy stress conditions
	maintain intracellular ATP level under conditions of energy stress
	is critical for cancer cell survival during metabolic stress, which can occur in the solid tumour microenvironment
	mediates spindle pole-associated MYL2(ser19) to control spindle orientation via regulation of actin cortex-astral microtubule attachments
	PRKAA1-dependent autophagy-mediated clearance of damaged mitochondria is required for erythrocyte maturation and homeostasis
	may play a role in the Hh signaling pathway, through which it regulates tumorigenesis
	PRKAA1 and PFKFB3 mediate glycolysis and survival in response to mitophagy during mitotic arrest
	is a key mediator linking obesity and impaired muscle regeneration
	play roles in regulating various cellular processes such as mitochondrial biogenesis

CELLULAR PROCESS	cell life, antiapoptosis

PHYSIOLOGICAL PROCESS

text	positive regulation of anti-apoptosis

PATHWAY

metabolism

lipid/lipoprotein

signaling

signal transduction

	fatty acid biosynthesis (positive regulation of fatty acid oxidation)
	cholesterol biosynthesis (positive regulation)
	steroid biosynthesis
	sterol biosynthesis
	negative regulation of glucosylceramide biosynthesis
	negative regulation of protein biosynthesis
	positive regulation of gluconeogenesis
	positive regulation of glucose import

a component	heterotrimer of a catalytic subunit (alpha), a beta and a gamma non-catalytic subunits
	catalytic subunit of the 5'-prime-AMP-activated protein kinase (AMPK)
	autophosphorylated

INTERACTION

DNA

RNA

small molecule	cofactor, nucleotide,
	ATP
	cAMP
	regulated by NME1 independently of the AMP concentration such that the manipulation of NME1 nucleotide trans-phosphorylation activity to generate ATP enhanced the activity of PRKAA1

protein	interacting with SPARC (SPARC may be involved in regulating glucose metabolism via PRKAA1 activation)
	PRKAA1, PRKAG1, PRKAB1 association with ULK1 plays an important role in autophagy induction, at least in part, by phosphorylation of raptor to lift the inhibitory effect of MTOR on the ULK1 autophagic complex
	CRBN directly interacts with the alpha1 subunit of AMP-activated protein kinase (PRKAA1) and inhibits the activation of AMPK activation
	PRKAA1 might regulate NADPH homeostasis by inhibiting ACACA and ACACB
	PRKAA1-mediated inhibition of ACACA is required to maintain the NADPH and reactive oxygen species levels after matrix detachment
	renin synthesis and secretion are regulated by PRKAA1 and coupled to metabolism by phosphorylation of ACACA
	is required for IL10 activation of the PI3K/AKT1/MTOR and STAT3-mediated anti-inflammatory pathways regulating macrophage functional polarization
	PRKAA1 stimulates ubiquitination of the gap junction protein GJA1, thereby contributing to gap junction remodeling following pressure overload
	PDLIM5 is a novel PRKAA1 substrate and it plays a critical role in the inhibition of cell migration
	reciprocal regulation of GPLD1 by PRKAA1 and regulation of PRKAA1 by GPLD1 and phosphatidic acid (PA)
	FNDC5 plays an important role in glucose metabolism via the ROS-mediated PRKAA1 pathway in skeletal muscle cells
	MAP3K11 serves as a common upstream kinase of PRKAA1 and JNK and functions as a direct upstream kinase for PRKAA1 independent of STK11
	PRKAA1-dependent phosphorylation of ULK1 is critical for translocation of ULK1 to mitochondria and for mitophagy in response to hypoxic stress
	regulation of DNM1L phosphorylation by PRKAA1 activation contributed to suppression of ER stress and thus presented a potential therapeutic strategy for PRKAA1 activation in the regulation of endothelium homeostasis

cell & other

REGULATION

activated by	cAMP
	LEP in skeletal muscle
	metformin, phenformin, and the AMP mimetic, 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR)

inhibited by

LEP in hypothalamus

Other

response to hypoxia

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional       gain of function PRKAA1 activation, during energy stress, prolongs cell survival by redox regulation constitutional       gain of function activation of PRKAA1 plays a critical role in TARDBP mislocalization and the development of ALS tumoral     --low   is associated with poor survival in melanoma patients

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed neurosensorial visual   PRKAA1 signaling pathway plays an important role in maintaining energy balance, and therefore may be a therapeutic target to prevent or delay retinal degeneration neurology neurodegenerative   may be a potential drug target for ALS

ANIMAL & CELL MODELS

prkaa1(-/-) mice manifest splenomegaly and anemia