PRKAG1 protein kinase, AMP-activated, gamma 1 non-catalytic subunit [Homo sapiens (human)] - Gene

Summary

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Official Symbol: PRKAG1provided by HGNC
Official Full Name: protein kinase, AMP-activated, gamma 1 non-catalytic subunitprovided by HGNC
Primary source: HGNC:9385
See related: Ensembl:ENSG00000181929; HPRD:04118; MIM:602742; Vega:OTTHUMG00000170406
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: AMPKG
Summary: The protein encoded by this gene is a regulatory subunit of the AMP-activated protein kinase (AMPK). AMPK is a heterotrimer consisting of an alpha catalytic subunit, and non-catalytic beta and gamma subunits. AMPK is an important energy-sensing enzyme that monitors cellular energy status. In response to cellular metabolic stresses, AMPK is activated, and thus phosphorylates and inactivates acetyl-CoA carboxylase (ACC) and beta-hydroxy beta-methylglutaryl-CoA reductase (HMGCR), key enzymes involved in regulating de novo biosynthesis of fatty acid and cholesterol. This subunit is one of the gamma regulatory subunits of AMPK. Alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

Genomic context

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Location :: 12q12-q14

Sequence :: Chromosome: 12; NC_000012.11 (49396055..49412629, complement)

See PRKAG1 in Epigenomics, MapViewer

Chromosome 12 - NC_000012.11 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Genomic Sequence

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Go to reference sequence details

Bibliography

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GeneRIFs: Gene References Into Functions What's a GeneRIF?

Studies suggest insights into the regulation of AMPK, its diverse biological actions, and therapeutic potential in the heart.
Title: AMP-activated protein kinase regulation and biological actions in the heart.
In breast cancer cells SESN2 is associated with AMPK.
Title: Sestrin2 modulates AMPK subunit expression and its response to ionizing radiation in breast cancer cells.
Conclude that cTnI phosphorylation by AMPK may represent a novel mechanism of regulation of cardiac function.
Title: AMP-activated protein kinase phosphorylates cardiac troponin I and alters contractility of murine ventricular myocytes.
Studies indicate that in most species, AMPK exists as an obligate heterotrimer, containing a catalytic subunit (alpha), and two regulatory subunits (beta and gamma).
Title: The AMPK signalling pathway coordinates cell growth, autophagy and metabolism.
Findings reveal that hypoxia can trigger AMPK activation in the apparent absence of increased [AMP] through ROS-dependent CRAC channel activation, leading to increases in cytosolic calcium that activate the AMPK upstream kinase CaMKKbeta.
Title: Hypoxia triggers AMPK activation through reactive oxygen species-mediated activation of calcium release-activated calcium channels.
Results suggest that AMPK association with ULK1 plays an important role in autophagy induction.
Title: The association of AMPK with ULK1 regulates autophagy.
Observational study of gene-disease association and gene-environment interaction. (HuGE Navigator)
Title: Common variants in 40 genes assessed for diabetes incidence and response to metformin and lifestyle intervention in the diabetes prevention program.
Observational study of gene-disease association. (HuGE Navigator)
Title: Investigation of genetic susceptibility factors for human longevity - a targeted nonsynonymous SNP study.
Observational study of gene-disease association, gene-gene interaction, gene-environment interaction, and genetic testing. (HuGE Navigator)
Title: Integrative predictive model of coronary artery calcification in atherosclerosis.
Inhibition of the KCa3.1 channels by AMP-activated protein kinase in human airway epithelial cells.
Title: Inhibition of the KCa3.1 channels by AMP-activated protein kinase in human airway epithelial cells.

Submit: New GeneRIF Correction See all (13)

Phenotypes

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Review eQTL and phenotype association data in this region using PheGenI

HIV-1 protein interactions

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Protein	Gene	Interaction	Pubs
Tat, p14	tat	Knockdown of SIRT1 by its inhibitor or siRNA results in Tat-mediated reduction of phosphorylation of AMP-activated protein kinase (AMPK) and downstream acetyl-CoA carboxylase (ACC)	PubMed
	tat	HIV-1 Tat induces IL-6 and TNF-alpha expression through the activation of cAMP-dependent protein kinase pathways	PubMed
Vif, p23	vif	Protein kinase A (PKA) binds and phosphorylates A3G at Thr32 in vitro and in vivo. This phosphorylation event reduces the binding of A3G to Vif and its subsequent ubiquitination and degradation	PubMed
Vpr, p15	vpr	HIV-1 Vpr directly interacts with PKA and is phosphorylated at position Ser79 by PKA. PKA activity is necessary for virion-delivered Vpr cell cycle arrest	PubMed
matrix	gag	HIV-1 MA increases phosphorylation and the DNA-binding activity of CREB and c-Myc through activation of the cAMP/PKA and MEK/ERK signaling pathways. Both signaling pathways are synergistically activated upon co-stimulation through the CD19 receptor	PubMed
	gag	HIV-1 Matrix impairs proliferation of normal lymphocytes in vitro by inducing the activity of the inhibitory protein kinase A (PKA)	PubMed
	gag	Protein kinase A (PKA) has been shown to phosphorylate HIV-1 Matrix in vitro	PubMed

Go to the HIV-1, Human Protein Interaction Database

Interactions

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Products	Interactant	Other Gene	Source	Pubs	Description
P54619	O15554	KCNN4	HPRD	PubMed
P54619	Q13131	PRKAA1	HPRD	PubMed
P54619	P54646	PRKAA2	HPRD	PubMed
P54619	Q9Y478	PRKAB1	HPRD	PubMed
P54619	O43741	PRKAB2	HPRD	PubMed
P54619	Q9UGJ0	PRKAG2	HPRD	PubMed
BioGRID:111558	BioGRID:126229	AP1S3	BioGRID	PubMed	Two-hybrid
BioGRID:111558	BioGRID:118855	BABAM1	BioGRID	PubMed	Affinity Capture-MS
BioGRID:111558	BioGRID:115889	CAMKK2	BioGRID	PubMed	Affinity Capture-MS
BioGRID:111558	BioGRID:108578	FKBP4	BioGRID	PubMed	Affinity Capture-MS
BioGRID:111558	BioGRID:125175	FNIP1	BioGRID	PubMed	Affinity Capture-MS; Affinity Capture-Western
BioGRID:111558	BioGRID:109315	HDAC1	BioGRID	PubMed	Negative Genetic
BioGRID:111558	BioGRID:110339	MCM2	BioGRID	PubMed	Affinity Capture-MS
BioGRID:111558	BioGRID:111075	PA2G4	BioGRID	PubMed	Affinity Capture-MS
BioGRID:111558	BioGRID:115852	PAICS	BioGRID	PubMed	Two-hybrid
BioGRID:111558	BioGRID:111251	PGK1	BioGRID	PubMed	Affinity Capture-MS
BioGRID:111558	BioGRID:111549	PRKAA1	BioGRID	PubMed	Affinity Capture-MS; Affinity Capture-Western; Two-hybrid
BioGRID:111558	BioGRID:111550	PRKAA2	BioGRID	PubMed	Affinity Capture-MS; Two-hybrid
BioGRID:111558	BioGRID:111551	PRKAB1	BioGRID	PubMed	Affinity Capture-MS; Two-hybrid
BioGRID:111558	BioGRID:111552	PRKAB2	BioGRID	PubMed	Affinity Capture-MS; Two-hybrid
BioGRID:111558	BioGRID:119531	PRKAG2	BioGRID	PubMed	Affinity Capture-MS; Two-hybrid
BioGRID:111558	BioGRID:112760	TARS	BioGRID	PubMed	Affinity Capture-MS
BioGRID:111558	BioGRID:113164	UBC	BioGRID	PubMed	Affinity Capture-MS
BioGRID:111558	BioGRID:113996	ULK1	BioGRID	PubMed	Affinity Capture-MS
BioGRID:111558	BioGRID:113258	VCP	BioGRID	PubMed	Affinity Capture-MS

Pathways from BioSystems

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AMPK signaling, organism-specific biosystem (from WikiPathways)
AMPK signaling, organism-specific biosystemAMPK signaling pathway, a fuel sensor and regulator, promotes ATP-producing and inhibits ATP-consuming pathways in various tissues. AMPK is a heterotrimer composed of alpha-catalytic and beta and gam...
Adipocytokine signaling pathway, organism-specific biosystem (from KEGG)
Adipocytokine signaling pathway, organism-specific biosystemIncreased adipocyte volume and number are positively correlated with leptin production, and negatively correlated with production of adiponectin. Leptin is an important regulator of energy intake and...
Adipocytokine signaling pathway, conserved biosystem (from KEGG)
Adipocytokine signaling pathway, conserved biosystemIncreased adipocyte volume and number are positively correlated with leptin production, and negatively correlated with production of adiponectin. Leptin is an important regulator of energy intake and...
Circadian rhythm, organism-specific biosystem (from KEGG)
Circadian rhythm, organism-specific biosystemCircadian rhythm is an internal biological clock, which enables to sustain an approximately 24-hour rhythm in the absence of environmental cues. In mammals, the circadian clock mechanism consists of ...
Circadian rhythm, conserved biosystem (from KEGG)
Circadian rhythm, conserved biosystemCircadian rhythm is an internal biological clock, which enables to sustain an approximately 24-hour rhythm in the absence of environmental cues. In mammals, the circadian clock mechanism consists of ...
Energy Metabolism, organism-specific biosystem (from WikiPathways)
Energy Metabolism, organism-specific biosystemThe PPARGC1A protein is a transcriptional coactivator that regulates the genes involved in energy metabolism. This protein interacts with the nuclear receptor PPARG, which permits the interaction of ...
Energy dependent regulation of mTOR by LKB1-AMPK, organism-specific biosystem (from REACTOME)
Energy dependent regulation of mTOR by LKB1-AMPK, organism-specific biosystemUpon formation of a trimeric LKB1:STRAD:MO25 complex, LKB1 phosphorylates and activates AMPK. If the AMP:ATP ratio rises, this activation is maintained and AMPK activates the TSC complex by phosphory...
Hypertrophic cardiomyopathy (HCM), organism-specific biosystem (from KEGG)
Hypertrophic cardiomyopathy (HCM), organism-specific biosystemHypertrophic cardiomyopathy (HCM) is a primary myocardial disorder with an autosomal dominant pattern of inheritance that is characterized by hypertrophy of the left ventricles with histological feat...
Hypertrophic cardiomyopathy (HCM), conserved biosystem (from KEGG)
Hypertrophic cardiomyopathy (HCM), conserved biosystemHypertrophic cardiomyopathy (HCM) is a primary myocardial disorder with an autosomal dominant pattern of inheritance that is characterized by hypertrophy of the left ventricles with histological feat...
IGF1R signaling cascade, organism-specific biosystem (from REACTOME)
IGF1R signaling cascade, organism-specific biosystemAfter autophosphorylation the type 1 insulin-like growth factor receptor (IGF1R) binds and phosphorylates scaffold proteins, IRS1/2/4 and SHC1, which in turn bind effectors possessing enzymatic activ...
IRS-mediated signalling, organism-specific biosystem (from REACTOME)
IRS-mediated signalling, organism-specific biosystemRelease of phospho-IRS from the insulin receptor triggers a cascade of signalling events via PI3K, SOS, RAF and the MAP kinases.
IRS-related events, organism-specific biosystem (from REACTOME)
IRS-related events, organism-specific biosystemIRS is one of the mediators of insulin signalling events. It is activated by phosphorylation and triggers a cascade of events involving PI3K, SOS, RAF and the MAP kinases. The proteins mentioned unde...
IRS-related events triggered by IGF1R, organism-specific biosystem (from REACTOME)
IRS-related events triggered by IGF1R, organism-specific biosystemThe phosphorylated type 1 insulin-like growth factor receptor phosphorylates IR1, IRS2, IRS4 and possibly other IRS/DOK family members (reviewed in Pavelic et al. 2007, Chitnis et al. 2008, Maki et a...
Insulin receptor signalling cascade, organism-specific biosystem (from REACTOME)
Insulin receptor signalling cascade, organism-specific biosystemAutophosphorylation of the insulin receptor triggers a series of signalling events, mediated by SHC or IRS, and resulting in activation of the Ras/RAF and MAP kinase cascades. A second effect of the ...
Insulin signaling pathway, organism-specific biosystem (from KEGG)
Insulin signaling pathway, organism-specific biosystemInsulin binding to its receptor results in the tyrosine phosphorylation of insulin receptor substrates (IRS) by the insulin receptor tyrosine kinase (INSR). This allows association of IRSs with the r...
Insulin signaling pathway, conserved biosystem (from KEGG)
Insulin signaling pathway, conserved biosystemInsulin binding to its receptor results in the tyrosine phosphorylation of insulin receptor substrates (IRS) by the insulin receptor tyrosine kinase (INSR). This allows association of IRSs with the r...
Membrane Trafficking, organism-specific biosystem (from REACTOME)
Membrane Trafficking, organism-specific biosystemThe secretory membrane system allows a cell to regulate delivery of newly synthesized proteins, carbohydrates, and lipids to the cell surface, a necessity for growth and homeostasis. The system is ma...
PI3K Cascade, organism-specific biosystem (from REACTOME)
PI3K Cascade, organism-specific biosystem
PI3K Cascade
PKB-mediated events, organism-specific biosystem (from REACTOME)
PKB-mediated events, organism-specific biosystemPKB and PDK1 are activated via membrane-bound PIP3. Activated PDK1 phosphorylates PKB, which in turn phosphorylates PDE3B. The latter hydrolyses cAMP to 5'AMP, depleting cAMP pools.
Regulation of AMPK activity via LKB1, organism-specific biosystem (from REACTOME)
Regulation of AMPK activity via LKB1, organism-specific biosystemLKB1 forms a complex with STRAD and MO25 thereby attaining a higher activity towards its substrates belonging to the subfamily of AMPK like kinases. LKB1:STRAD:MO25 complex phosphorylates AMPK consta...
Regulation of Rheb GTPase activity by AMPK, organism-specific biosystem (from REACTOME)
Regulation of Rheb GTPase activity by AMPK, organism-specific biosystemActivated AMPK phosphorylates TSC2 and activates the TSC complex. TSC2 functions as a GTPase-activating protein and stimulates the intrinsic GTPase activity of a small G-protein Rheb. This results in...
Signal Transduction, organism-specific biosystem (from REACTOME)
Signal Transduction, organism-specific biosystemSignal transduction is a process in which extracellular signals elicit changes in cell state and activity. Transmembrane receptors sense changes in the cellular environment by binding ligands, such a...
Signaling by Insulin receptor, organism-specific biosystem (from REACTOME)
Signaling by Insulin receptor, organism-specific biosystemInsulin binding to its receptor results in receptor autophosphorylation on tyrosine residues and the tyrosine phosphorylation of insulin receptor substrates (e.g. IRS and Shc) by the insulin receptor...
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R), organism-specific biosystem (from REACTOME)
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R), organism-specific biosystemBinding of IGF1 (IGF-I) or IGF2 (IGF-II) to the extracellular alpha peptides of the type 1 insulin-like growth factor receptor (IGF1R) triggers the activation of two major signaling pathways: the SOS...
TOR signaling, organism-specific biosystem (from WikiPathways)
TOR signaling, organism-specific biosystemTOR signaling is responsible for a cellular reaction towards nutrient and energy availability and hypoxia/stress. The mammalian Target Of Rapamycin (mTOR), a serine/threonine kinase, is the central r...
Translocation of GLUT4 to the Plasma Membrane, organism-specific biosystem (from REACTOME)
Translocation of GLUT4 to the Plasma Membrane, organism-specific biosystemIn adipocytes and myocytes insulin signaling causes intracellular vesicles carrying the GLUT4 glucose transporter to translocate to the plasma membrane, allowing the cells to take up glucose from the...
mTOR signalling, organism-specific biosystem (from REACTOME)
mTOR signalling, organism-specific biosystem
mTOR signalling

General gene information

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Markers

WI-19311 (e-PCR)
- UniSTS:3000

SHGC-33837 (e-PCR)
- UniSTS:78289

RH11260 (e-PCR)
- UniSTS:79868

Homology

Homologs of the PRKAG1 gene: The PRKAG1 gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, and C.elegans.
Map Viewer (Mouse, Rat)

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
ADP binding	ISS Inferred from Sequence or Structural Similarity more info
AMP binding	ISS Inferred from Sequence or Structural Similarity more info
contributes_to AMP-activated protein kinase activity	ISS Inferred from Sequence or Structural Similarity more info
ATP binding	ISS Inferred from Sequence or Structural Similarity more info
cAMP-dependent protein kinase activity	TAS Traceable Author Statement more info	PubMed
cAMP-dependent protein kinase regulator activity	TAS Traceable Author Statement more info	PubMed
protein binding	IPI Inferred from Physical Interaction more info	PubMed
protein kinase activity	IDA Inferred from Direct Assay more info	PubMed
protein kinase binding	IDA Inferred from Direct Assay more info	PubMed

Process	Evidence Code	Pubs
cell cycle arrest	TAS Traceable Author Statement more info
cellular membrane organization	TAS Traceable Author Statement more info
fatty acid biosynthetic process	IEA Inferred from Electronic Annotation more info
insulin receptor signaling pathway	TAS Traceable Author Statement more info
positive regulation of gene expression	IDA Inferred from Direct Assay more info	PubMed
positive regulation of protein kinase activity	TAS Traceable Author Statement more info	PubMed
protein phosphorylation	IDA Inferred from Direct Assay more info	PubMed
regulation of glycolysis	TAS Traceable Author Statement more info	PubMed
signal transduction	TAS Traceable Author Statement more info	PubMed
spermatogenesis	TAS Traceable Author Statement more info	PubMed

Component	Evidence Code	Pubs
AMP-activated protein kinase complex	ISS Inferred from Sequence or Structural Similarity more info
cytosol	TAS Traceable Author Statement more info

General protein information

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Preferred Names: 5'-AMP-activated protein kinase subunit gamma-1

Names: 5'-AMP-activated protein kinase subunit gamma-1; AMPK gamma1; AMPK gamma-1 chain; 5'-AMP-activated protein kinase, gamma-1 subunit

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

mRNA and Protein(s)

NM_001206709.1 → NP_001193638.1 5'-AMP-activated protein kinase subunit gamma-1 isoform 3

Status: REVIEWED

Description

Transcript Variant: This variant (3) uses an alternate in-frame splice site in the central coding region, compared to variant 1, resulting in an isoform (3) that is longer than isoform 1.

Source sequence(s)

AK097606, BC000358, BM667691, DB020277

Consensus CDS

CCDS55825.1

UniProtKB/Swiss-Prot

P54619

UniProtKB/TrEMBL

Q8N7V9

Related

ENSP00000323867, OTTHUMP00000243708, ENST00000316299, OTTHUMT00000408945

Conserved Domains (3) summary

COG0517
Location:212 – 328
Blast Score: 109

COG0517; FOG: CBS domain [General function prediction only]

cd04618
Location:46 – 184
Blast Score: 295

CBS_pair_5; The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called ...

cd04641
Location:211 – 330
Blast Score: 416

CBS_pair_28; The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called ...
NM_001206710.1 → NP_001193639.1 5'-AMP-activated protein kinase subunit gamma-1 isoform 4

Status: REVIEWED

Description

Transcript Variant: This variant (4) differs in the 5' UTR and uses a downstream in-frame start codon, compared to variant 1. The encoded isoform (4) is shorter at the N-terminus, compared to isoform 1.

Source sequence(s)

AK293332, BC000358, BM667691

Consensus CDS

CCDS55824.1

UniProtKB/TrEMBL

B4DDT7

UniProtKB/Swiss-Prot

P54619

Related

ENSP00000448972, OTTHUMP00000243712, ENST00000552212, OTTHUMT00000408949

Conserved Domains (3) summary

COG0517
Location:171 – 287
Blast Score: 107

COG0517; FOG: CBS domain [General function prediction only]

cd04618
Location:14 – 143
Blast Score: 312

CBS_pair_5; The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called ...

cd04641
Location:170 – 289
Blast Score: 415

CBS_pair_28; The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called ...
NM_002733.4 → NP_002724.1 5'-AMP-activated protein kinase subunit gamma-1 isoform 1

Status: REVIEWED

Description

Transcript Variant: This variant (1) encodes isoform 1.

Source sequence(s)

BC000358, BM667691, DB020277

Consensus CDS

CCDS8777.1

UniProtKB/Swiss-Prot

P54619

Related

ENSP00000447433, OTTHUMP00000243709, ENST00000548065, OTTHUMT00000408946

Conserved Domains (3) summary

COG0517
Location:203 – 319
Blast Score: 109

COG0517; FOG: CBS domain [General function prediction only]

cd04618
Location:46 – 175
Blast Score: 316

CBS_pair_5; The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called ...

cd04641
Location:202 – 321
Blast Score: 416

CBS_pair_28; The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called ...

RefSeqs of Annotated Genomes: Homo sapiens Annotation Release 104

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh37.p10 Primary Assembly

Genomic

NC_000012.11 Reference GRCh37.p10 Primary Assembly

Range

49396055..49412629, complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Alternate HuRef

Genomic

AC_000144.1 Alternate HuRef

Range

46427570..46444145, complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Alternate CHM1_1.0

Genomic

NC_018923.1 Alternate CHM1_1.0

Range

49229069..49245643, complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Suppressed Reference Sequence(s)

The following Reference Sequences have been suppressed. Explain

NM_212461.1: Suppressed sequence

Description

NM_212461.1: This RefSeq was permanently suppressed because currently there is insufficient support for the transcript and the protein.

Nucleotide		Protein
Heading	Accession and Version	Protein
genomic	ABBA01031498.1 (24409..40984)	None
genomic	AC011603.37 (140110..156647)	None
genomic	AMYH01004437.1 (2908..19482)	None
genomic	CH471111.1	EAW58032.1
		EAW58033.1
mRNA	AK097606.1	BAC05117.1
mRNA	AK293332.1	BAG56848.1
mRNA	AK303276.1	BAG64356.1
mRNA	AK307994.1	None
mRNA	AK310250.1	None
mRNA	BC000358.2	AAH00358.1
mRNA	BG772337.1	None
mRNA	BG772412.1	None
mRNA	BI757340.1	None
mRNA	BM667691.1	None
mRNA	BM972308.1	None
mRNA	BT007345.1	AAP36009.1
mRNA	CB124830.1	None
mRNA	DB020277.1	None