Abstract
Chronic inflammation (CI) is a primary contributing factor involved in multiple diseases like cancer, stroke, diabetes, Alzheimer’s disease, allergy, asthma, autoimmune diseases, coeliac disease, glomerulonephritis, sepsis, hepatitis, inflammatory bowel disease, reperfusion injury, and transplant rejections. Despite several expansions in our understanding of inflammatory disorders and their mediators, it seems clear that numerous proteins participate in the onset of CI. One crucial protein pyruvate kinase M2 (PKM2) much studied in cancer is also found to be inextricably woven in the onset of several CI’s. It has been found that PKM2 plays a significant role in several disorders using a network of proteins that interact in multiple ways. For instance, PKM2 forms a close association with epidermal growth factor receptors (EGFRs) for uncontrolled growth and proliferation of tumor cells. In neurodegeneration, PKM2 interacts with apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) to onset Alzheimer’s disease pathogenesis. The cross-talk of protein tyrosine phosphatase 1B (PTP1B) and PKM2 acts as stepping stones for the commencement of diabetes. Perhaps PKM2 stores the potential to unlock the pathophysiology of several diseases. Here we provide an overview of the notoriously convoluted biology of CI’s and PKM2. The cross-talk of PKM2 with several proteins involved in stroke, Alzheimer’s, cancer, and other diseases has also been discussed. We believe that considering the importance of PKM2 in inflammation-related diseases, new options for treating various disorders with the development of more selective agents targeting PKM2 may appear.
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Abbreviations
- 3PO:
-
3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one
- AD:
-
Alzheimer’s disease
- ADP:
-
adenosine diphosphate
- Akt:
-
protein kinase B or PKB
- AMPK:
-
adenosine monophosphate-activated protein kinase
- Ang-1:
-
angiopoietin-1
- APE1:
-
apurinic/apyrimidinic endodeoxyribonuclease 1
- ApoE:
-
apolipoprotein E
- ATP:
-
adenosine triphosphate
- Bcl-2:
-
B cell lymphoma 2
- Bcl-xl:
-
B cell lymphoma-extra large
- Bcr-Abl:
-
breakpoint cluster region - Abelson gene (fusion of gene) sequence
- Bmal:
-
brain and muscle ARNT-like protein
- BRAF:
-
proto-oncogene B-Raf & v-Raf murine sarcoma viral oncogene homolog B, serine/threonine-protein kinase B-Raf
- CAD:
-
coronary artery disease
- CCI:
-
chronic constriction injury
- CCL:
-
chemokine (c-c motif) ligand
- CD:
-
Crohn’s disease
- CDK4:
-
cyclin-dependant kinase 4
- CI:
-
chronic inflammation
- CNS:
-
central nervous system
- COL2A1:
-
collagen type 2 alpha 1 chain
- CRAF:
-
RAF proto-oncogene serine/threonine-protein kinase
- CSC:
-
cancer stem cell
- CUL3:
-
Cullin-3
- CXCL:
-
chemokine (C-X-C motif) ligand
- CXCR4:
-
C-X-C chemokine receptor type 4
- Cys:
-
3-letter code for amino acid cysteine
- DAPK:
-
death-associated protein kinase
- DBD:
-
DNA-binding domain
- DNA:
-
deoxyribonucleic acid
- DRAK:
-
death-associated protein kinase related
- DU145:
-
a human prostate cancer cell line
- EGF:
-
epidermal growth factor
- EGFR:
-
epidermal growth factor receptor
- EIF2AK2:
-
eukaryotic translation initiation factor 2-alpha kinase 2
- EMT:
-
epithelial-mesenchymal transitions
- e-NOS:
-
endothelial Nitric oxide synthase
- EPO:
-
erythropoietin
- ERK:
-
extracellular signal-regulated kinases
- EVs:
-
extracellular vesicles
- FAK:
-
focal adhesion kinase
- FDA or USFDA:
-
United States Food & Drug Administration
- FH:
-
fumarate dehydrogenase
- G12V:
-
glycine is mutated by Valine at the residue no. 12
- GLUT:
-
glucose transporter
- GM-CSF:
-
granulocyte-macrophage colony-stimulating factor
- GSK:
-
glycogen synthase kinase
- GTPase:
-
guanosine triphosphatase
- HER2:
-
human epidermal growth factor receptor 2
- HHcy:
-
hyperhomocysteinemia
- HI:
-
hypoxia-Ischemia
- HIF:
-
hypoxia including factor
- HMGB1:
-
high mobility group box 1 protein
- HRE:
-
hypoxia-responsive element
- HSP:
-
heat shock proteins
- I2H:
-
in silico 2-hybrid
- IBD:
-
inflammatory bowel disease
- ICAM-1:
-
intercellular adhesion molecule 1
- IFN:
-
interferon
- IGF:
-
insulin-like growth factor
- IgG:
-
immunoglobulin G
- IKKβ:
-
inhibitor of nuclear factor kappa-B kinase subunit beta
- IL:
-
interleukin
- iNOS:
-
inducible nitric oxide synthase
- JMJD5:
-
jumonji C domain-containing deoxygenase 5 protein
- JNK:
-
c-Jun N-terminal kinase
- K433:
-
1-letter code for amino acid lysine including its residue no. 433
- LDHA, LDA-A:
-
lactate dehydrogenase A
- LKB1:
-
liver kinase B1
- LPS:
-
lipopolysaccharide
- MAK:
-
mitogen-activated protein kinases (MAP kinase/MAPK)
- MCP:
-
monocyte chemoattractant protein
- MCT:
-
monocarboxylate transporter
- MDA-MB-231:
-
an epithelial human breast cancer cell line
- MDSC:
-
myeloid-derived suppressor cells
- MEK:
-
a type of serine/tyrosine/threonine kinase & one of the mitogen-activated kinases
- MET:
-
tyrosine-protein kinase Met or hepatocyte growth factor receptor (HGFR)
- MLC:
-
myosin light chain
- mRNA:
-
messenger RNA
- mtDNA:
-
mitochondrial DNA
- mTOR:
-
mammalian target for Rapamycin or mechanistic target for Rapamycin
- mTORC1:
-
mammalian target for Rapamycin complex 1 or mechanistic target for Rapamycin complex 1
- nDNA:
-
nuclear DNA
- NFκB:
-
nuclear factor kappa B
- NOX4:
-
NADPH oxidase 4
- OA:
-
osteoarthritis
- Oct:
-
octamer-binding transcription factor
- OSM:
-
oncostatin M
- OXPHOS:
-
oxidative phosphorylation
- P2X receptors:
-
purinergic receptors X
- P2Y receptors:
-
purinergic receptors Y
- p300:
-
epigenetic cofactor
- P-38:
-
a class of mitogen-activated protein kinases
- PAMP:
-
pathogen-associated molecular pattern
- PDAC:
-
pancreatic ductal adenocarcinoma
- PDK:
-
pyruvate dehydrogenase kinase
- PEP:
-
phosphoenolpyruvate
- PFKFB3:
-
6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3
- PGHS:
-
prostaglandin endoperoxide H synthase
- PHD:
-
prolyl hydroxylase
- PI3K:
-
phosphoinositide 3-kinase or phosphatidylinositol 3-kinase
- PK:
-
pyruvate kinase
- PKC:
-
protein kinase C
- PKL:
-
pyruvate kinase L isoform
- PKLR:
-
pyruvate kinase LR gene
- PKM:
-
pyruvate kinase M gene
- PKM1:
-
pyruvate kinase M1 isoform
- PKM2:
-
pyruvate kinase M2 isoform
- PKR:
-
pyruvate kinase R isoform
- PPI:
-
protein–protein interaction
- PPP:
-
pentose phosphate pathway
- PROTAC:
-
proteolysis targeting chimera
- PRR:
-
pattern recognition receptors
- PsA:
-
psoriatic arthritis
- PTB:
-
polypyrimidine tract-binding protein
- PTP1B:
-
protein–tyrosine phosphatase 1B
- RA:
-
rheumatoid arthritis
- Ral (RalA and RalB):
-
Ras-related protein RalA and RalB
- RASFC:
-
rheumatoid arthritis-synovial fibroblast cells
- Ras-Raf-MEK-ERK pathway:
-
also known as MAPK/ERK pathway
- RET/PTC1:
-
rearranged during transfection/papillary thyroid carcinoma 1
- RNA:
-
ribonucleic acid
- ROCK2:
-
Rho-associated protein kinase
- ROS:
-
reactive oxygen species
- S15:
-
1-letter code for amino acid Serine including its residue no. 15
- SDF:
-
stromal cell–derived factor
- SDH:
-
succinate dehydrogenase
- Ser:
-
3-letter code for amino acid Serine
- SOX-9:
-
a transcription factor
- STAT:
-
signal transducer and activator of transcription proteins
- SUMOlyation:
-
small ubiquitin-like modification
- T45:
-
1-letter code for amino acid Threonine including its residue no. 45
- TAD:
-
transcriptional activation domain
- TAP-MS:
-
tandem affinity purification-mass spectroscopy
- TBK1:
-
TANK-binding kinase 1
- TCA:
-
tricarboxylic acid
- TGFIF2:
-
TGF-β induced factor homeobox-2
- TGF-β :
-
transforming growth factor β
- Tie-2:
-
angiopoietin-1 receptor
- TLR:
-
Toll-like receptors
- TNF:
-
tumour necrosis factor
- Tyr:
-
3-letter code of amino acid tyrosine
- U251:
-
a human brain cell line
- UC:
-
ulcerative colitis
- VCAM-1:
-
vascular cell adhesion protein 1
- VEGF:
-
vascular endothelial growth factor
- Y105F:
-
tyrosine is mutated with phenylalanine at the residue no. 105
- Y118:
-
1-letter code for amino acid tyrosine including its residue no. 118
- Y2H:
-
yeast 2-hybrid
- Y333:
-
1-letter code of amino acid tyrosine including its residue no. 333
- αSyn:
-
α-synuclein
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The authors gratefully acknowledge Director, NIPER-Ahmedabad for her support and encouragement. The communication number for publication is NIPER-A/438/5/2020. Authors SP, AD, PM, AS, AC, HJ, AD, DS, and LVN are thankful to NIPER-Ahmedabad, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Government of India for their fellowships.
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Dr. Amit Shard designed the concept of the protein–protein interaction and role in cancer. Sagarkumar Patel and Dr. Amit Shard wrote the role of PKM2 in chronic inflammation and cancer. Sagarkumar Patel, Anwesha Das, Payal Meshram, Ayushi Sharma, and Arnab Chowdhury helped in the literature search and data collection. Heena Jariyal and Dr. Akshay Srivastava wrote the role of glycolysis in cancer. Aishika Datta, Deepaneeta Sarmah, and Dr. Pallab Bhattacharya wrote the role of PKM2 in ischemic stroke. Lakshmi Vineela and Dr. Amit Khairnar wrote the role of the PKM2 in inflammatory diseases. Dr. Bichismita Sahu wrote the role of the PKM2 in Alzheimer’s disease. All authors read and approved the final version of the manuscript.
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Patel, S., Das, A., Meshram, P. et al. Pyruvate kinase M2 in chronic inflammations: a potpourri of crucial protein–protein interactions. Cell Biol Toxicol 37, 653–678 (2021). https://doi.org/10.1007/s10565-021-09605-0
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DOI: https://doi.org/10.1007/s10565-021-09605-0