Biomarker: PKM2

Histology type: endometrial carcinoma

Stage: high risk

Country: China

Region: Shanghai 

Followed up time :

Subgroup 1 name : positive

Subgroup 1 number: 65

Subgroup 2 name: negative

Subgroup 2 number: 54

Conclusion: PKM2 may play an important role in the progression of EC. It is potential biomarkers to better predict high-risk EC;thereby guide clinical therapy.

Sample type : tissue

Sample method: immunohistochemical/two-dimensional gel electrophoresis (2-DE);a liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) proteomics approach

Expression pattern : positive expression

Expression elevation: For semiquantitative assessment of the immunohistochemical results, the mean percentage of positive tumor cells was determined in at least 10 random fields at ×400 magnification in each section and graded as focal (≤10%), regional (11%–50%), or diffuse (>50%). The intensity of the PKM2 and HSPA5 immunoreaction was graded weak, moderate, or intense. The mean percentage of positive tumor cells and the staining intensity were then combined to produce an IHC result. Cases that graded ‘intense diffuse, intense regional, moderate diffuse, and moderate regional’ were considered positive; others were considered negative.

Statictics: Mean ;Range

Cohort age: 60.2;36–89

Funtion Uniprot: Catalyzes the final rate-limiting step of glycolysis by mediating the transfer of a phosphoryl group from phosphoenolpyruvate (PEP) to ADP, generating ATP (PubMed:20847263, PubMed:15996096, PubMed:1854723). The ratio between the highly active tetrameric form and nearly inactive dimeric form determines whether glucose carbons are channeled to biosynthetic processes or used for glycolytic ATP production (PubMed:20847263, PubMed:15996096, PubMed:1854723). The transition between the 2 forms contributes to the control of glycolysis and is important for tumor cell proliferation and survival (PubMed:20847263, PubMed:15996096, PubMed:1854723).3 Publications Isoform M2 Isoform specifically expressed during embryogenesis that has low pyruvate kinase activity by itself and requires allosteric activation by D-fructose 1,6-bisphosphate (FBP) for pyruvate kinase activity (PubMed:18337823, PubMed:20847263). In addition to its pyruvate kinase activity in the cytoplasm, also acts as a regulator of transcription in the nucleus by acting as a protein kinase (PubMed:18191611, PubMed:21620138, PubMed:22056988, PubMed:22306293, PubMed:22901803, PubMed:24120661). Translocates into the nucleus in response to various signals, such as EGF receptor activation, and homodimerizes, leading to its conversion into a protein threonine- and tyrosine-protein kinase (PubMed:22056988, PubMed:22306293, PubMed:22901803, PubMed:24120661, PubMed:26787900). Catalyzes phosphorylation of STAT3 at 'Tyr-705' and histone H3 at 'Thr-11' (H3T11ph), leading to activate transcription (PubMed:22306293, PubMed:22901803, PubMed:24120661). Its ability to activate transcription plays a role in cancer cells by promoting cell proliferation and promote tumorigenesis (PubMed:18337823, PubMed:22901803, PubMed:26787900). Promotes the expression of the immune checkpoint protein CD274 in ARNTL/BMAL1-deficient macrophages (By similarity). May also act as a translation regulator for a subset of mRNAs, independently of its pyruvate kinase activity: associates with subpools of endoplasmic reticulum-associated ribosomes, binds directly to the mRNAs translated at the endoplasmic reticulum and promotes translation of these endoplasmic reticulum-destined mRNAs (By similarity). Plays a role in caspase independent cell death of tumor cells (PubMed:17308100).By Similarity10 Publications Isoform M1 Pyruvate kinase isoform expressed in adult tissues, which replaces isoform M2 after birth (PubMed:18337823). In contrast to isoform M2, has high pyruvate kinase activity by itself and does not require allosteric activation by D-fructose 1,6-bisphosphate (FBP) for activity (PubMed:20847263).2 Publications

UniProt ID: P14618

UniProt Link: https://www.uniprot.org/uniprotkb/P14618/entry

Biological function from UniProt: #Glycolysis #Translation regulation

Molecular function from UniProt:

Tissue specificity from UniProt: Isoform M2 Specifically expressed in proliferating cells, such as embryonic stem cells, embryonic carcinoma cells, as well as cancer cells. Isoform M1 Expressed in adult tissues (PubMed:18337823). Not expressed in tumor cells (PubMed:18337823).

Subcellular UniProt: #Cytoplasm #Nucleus

Alternative name from UniProt:

Miscellaneous: There are 4 isozymes of pyruvate kinase in mammals (L, R, M1, M2) encoded by 2 different genes: PKLR and PKM. The L and R isozymes are generated from the PKLR by differential splicing of RNA; the M1 and M2 forms are produced from the PKM gene by differential splicing. L type is major isozyme in the liver, R is found in red cells, M1 is the main form in muscle, heart and brain, and M2 is found in early fetal tissues as well as in most cancer cells.

Catalytic activity: ATP + pyruvate = ADP + H+ + phosphoenolpyruvate This reaction proceeds in the backward direction;Isoform M2 :ATP + L-tyrosyl-[protein] = ADP + H+ + O-phospho-L-tyrosyl-[protein] This reaction proceeds in the forward direction.;Isoform M1 ATP + pyruvate = ADP + H+ + phosphoenolpyruvate;

Activity regulation: Isoform M2 Isoform M2 is allosterically activated by D-fructose 1,6-bisphosphate (FBP) (PubMed:2813362, PubMed:15996096, PubMed:1854723, PubMed:18337815). Inhibited by oxalate and 3,3',5-triiodo-L-thyronine (T3) (PubMed:15996096). The activity of the tetrameric form is inhibited by PML (PubMed:18298799). Selective binding to tyrosine-phosphorylated peptides releases the allosteric activator FBP, leading to inhibition of PKM enzymatic activity, this diverts glucose metabolites from energy production to anabolic processes when cells are stimulated by certain growth factors (PubMed:18337815). Glycolytic flux are highly dependent on de novo biosynthesis of serine and glycine, and serine is a natural ligand and allosteric activator of isoform M2 (PubMed:23064226). Acetylation at Lys-433 promotes its translocation into the nucleus and homodimerization, promoting the protein kinase activity (PubMed:24120661).7 Publications Isoform M1 Has high pyruvate kinase activity by itself and does not require allosteric activation by D-fructose 1,6-bisphosphate (FBP) for activity.

Recommended name: Pyruvate kinase PKM

Gene name from HGNC: PKM (OIP3, PK3, PKM2, THBP1)

HPA class: Cancer-related genes Enzymes Metabolic proteins Plasma proteins

AlphaFold DB: P14618

AlphaFold Link: https://alphafold.ebi.ac.uk/entry/P14618

Developmental stage: Isoform M2 Specifically expressed during embryonic development. Isoform M1 Specifically expressed in adult tissues

HPA link: https://www.proteinatlas.org/ENSG00000067225-PKM

Tissue specificity RNA from HPA: Tissue enhanced (skeletal muscle, tongue)

Tissue expression from HPA: Cancer-related genes Enzymes Metabolic proteins Plasma proteins

Single cell type specificity Cell type enhanced (Basal respiratory cells, Late spermatids)

Immune cell specificity: Low immune cell specificity

Subcellular summary HPA Located in Cytosol (Single cell variability)

Cancer prognostic summary HPA Prognostic marker in liver cancer (unfavorable), pancreatic cancer (unfavorable), head and neck cancer (unfavorable) and lung cancer (unfavorable)

Pathology link: https://www.proteinatlas.org/ENSG00000067225-PKM/pathology

Pathology endo: https://www.proteinatlas.org/ENSG00000067225-PKM/pathology/endometrial+cancer

OMIM: 179050

OMIM link2: https://www.omim.org/entry/179050

HGNC ID: HGNC:9021

HGNC link: https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:9021