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FLASH GENE

Symbol

PKM

contributors: mct/npt/pgu - updated : 03-09-2016

HGNC name	pyruvate kinase, muscle
HGNC id	9021

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Location	15q23      Physical location : -
Synonym name	OPA-interacting protein 3
	pyruvate kinase M2
	thyroid hormone-binding protein, cytosolic pyruvate kinase M2
Synonym symbol(s)	PK3, TCB, OIP3, CTHBP, THBP2, THBP1, MGC3932, PKM2
EC.number	2.7.1.40

DNA

TYPE	functioning gene
STRUCTURE	32.53 kb     11 Exon(s)

text structure

putative Sp1-binding sites

MAPPING

cloned

Y

linked

N

status

confirmed

RNA

TRANSCRIPTS	type	messenger

text

two alternatively spliced isoforms, M1 and M2 alternative splicing has an important role in determining the metabolic phenotype of mammalian cells (PMID: 20010808) exons 9 and 10 are alternatively spliced in a mutually exclusive fashion to give rise to the PK-M1 and PK-M2 isoforms, respectively (PMID: 20133837)

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_002654 11 splicing 2516 NP_002645 58 531 . upregulated in cancer cells . expressed during development and in many adult tissues, including the spleen, lung, and all cancers . present in some glial cells and rod and cone photoreceptors in the retina of all species but was exclusively localized to glia in the brain 2013 24120138 lacking a segment within the 5' UTR compared to variant 2 variant PKM2, embryonic pyruvate kinase isoform, almost universally re-expressed in cancer, and promoting aerobic glycolysis inclusion of exon 10 PKM2, but not PKM1, is regulated by the binding of tyrosine phosphorylated peptides, which results in release of the allosteric activator fructose-1-6-bisphosphate and inhibition of pyruvate kinase activity activity of PK-M2 is allosterically regulated by fructose-1,6-bisphosphate levels and interaction with tyrosine-phosphorylated proteins NM_182470 11 splicing 2732 NP_872270 58 531 . predominantly in differentiated adult tissues with high ATP requirements, such as the heart, brain, and muscle . confined to neurons in the retina and brain 2013 24120138 representing the longest transcript encoding an isoform (2) that is the same length as isoform 1, but containing a different internal segment variant PKM1, adult isoform, promoting oxidative phosphorylation inclusion of exon 9 constitutively active NM_182471 12 splicing 2516 NP_872271 57 531 - 2012 23155487 lacking a segment in the 5' UTR having an alternate in-frame coding exon compared to variant 2 resulting in an isoform (1) with a different internal segment than isoform 2, but being the same length NM_001206797 10 - 2294 NP_001193726 - 457 - 2012 23155487 NM_001206798 11 - 2541 NP_001193727 - 516 - 2012 23155487 NM_001206796 12 - 2853 NP_001193725 - 605 - 2012 23155487 NM_001206799 11 - 2421 NP_001193728 - 536 - 2012 23155487

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 Digestive pancreas exocrine       moderately Nervous brain         Homo sapiens Reproductive female system ovary     highly   female system uterus cervix   highly Skin/Tegument skin       predominantly Urinary kidney       moderately Visual eye retina       Homo sapiens

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Nervous peripherous

cells

System Cell Pubmed Species Stage Rna symbol Nervous neuron Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains

mono polymer

homomer , tetramer

HOMOLOGY

interspecies	ortholog to rattus Pkm2
	ortholog to murine Pkm2
	ortholog to zebrafish pkm2
	ortholog to drosophila PyK
	ortholog to S. cerevisiae CDC19

Homologene

FAMILY

pyruvate kinase family

CATEGORY

enzyme

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,cytosolic

basic FUNCTION	catalyzing the production of phosphoenolpyruvate from pyruvate and ATP
	may mediate cellular metabolic effects induced by thyroid hormones
	phosphotyrosine-binding form of pyruvate kinase which is critical for rapid growth in cancer cells
	essential non-metabolic functions of PKM (isoform PKM2) in EGFR-promoted CTNNB1 transactivation, cell proliferation and tumorigenesis
	role as a protein kinase in its nonmetabolic functions of histone modification, which is essential for its epigenetic regulation of gene expression and tumorigenesis
	plays an important role in the growth and metabolic reprogramming of cancer cells in stress conditions
	importance of nuclear functions of PKM2 in the Warburg effect and tumorigenesis

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

carbohydrate , energetic

signaling

	glycolysis, final step
	energy pathway

a component	PKM dimer is an active protein kinase, while the tetramer is an active pyruvate kinase
	PKM/TGM2 interplay plays an important role in the regulation of autophagy in particular under cellular stressful conditions such as those displayed by cancer cells

INTERACTION

DNA

RNA

small molecule	cofactor,
	Mg2+
	K+

protein	binds directly and selectively to tyrosine-phosphorylated peptides
	OPA protein
	interacting with HNRNPA2B1, PTBP1, and HNRNPA1 (have critical role in promoting PKM2 production in tumours, and overexpression of some combination of them is, like PKM2 expression, likely to be a general phenomenon in cancer
	interaction with PKM2, and inhibition of PKM2 by PRL contributes potentially to the PRL-stimulated cell proliferation
	SAICAR stimulates PKM and promotes cancer cell survival in glucose-limited conditions
	KDM8/PKM interaction resides at the intersubunit interface region of PKM, which hinders PKM tetramerization and blocks pyruvate kinase activity
	ZBTB7A directly binds to the promoter and represses the transcription of critical glycolytic genes, including SLC2A3, PFKP, and PKM
	TRIM35 interacts with PKM and the coiled-coil domain is required for such an interaction
	ECM1 plays an important role in promoting the Warburg effect mediated by PKM
	TRIM35 inhibits phosphorylation of pyruvate kinase isoform M2 (PKM), which is involved in aerobic glycolysis of cancer cells
	TGM2 interacts with PKM, a rate limiting enzyme of glycolysis which is responsible for maintaining a glycolytic phenotype in malignant cells and displays non metabolic functions, including transcriptional co-activation and protein kinase activity
	PKM activates MTOR signaling through phosphorylating MTOR inhibitor AKT1 substrate 1 (AKT1S1)

cell & other

serine can bind to and activate PKM2, and PKM2 activity in cells is reduced in response to serine deprivation

REGULATION

Other

regulation of PKM activity supports the different metabolic requirements of proliferating and nonproliferating tumor cells

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --over   in gastric cancer tumoral     --over   with MYC, PTBP1, HNRNPA1 and HNRNPA2B1 in gliomas, correlated with PKM2 expression tumoral     --over   in a grade-specific manner in human glioma

Susceptibility

Variant & Polymorphism

Candidate gene
Marker	PKM/TRIM35 expression could be a biomarker for the prognosis of hepatocellular carcinoma (HCC)
Therapy target
	System Type Disorder Pubmed cancer     because most normal tissues express an isoform of pyruvate kinase other than PKM2, selective targeting of PKM2 provides an opportunity to target cell metabolism for cancer therapy

ANIMAL & CELL MODELS