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Pyruvate kinase M2 in chronic inflammations: a potpourri of crucial protein–protein interactions

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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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Acknowledgements

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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Author notes

  1. Sagarkumar Patel and Anwesha Das contributed equally to this work.

Authors and Affiliations

  1. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Ahmedabad, Opposite Air Force Station, Gandhinagar, Gujarat, 382355, India

    Sagarkumar Patel, Anwesha Das, Payal Meshram, Ayushi Sharma, Arnab Chowdhury, Bichismita Sahu & Amit Shard

  2. Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Ahmedabad, Opposite Air Force Station, Gandhinagar, Gujarat, 382355, India

    Heena Jariyal

  3. Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Ahmedabad, Opposite Air Force Station, Gandhinagar, Gujarat, 382355, India

    Aishika Datta, Deepaneeta Sarmah, Lakshmi Vineela Nalla, Amit Khairnar & Pallab Bhattacharya

  4. Department of Medical Devices, National Institute of Pharmaceutical Education and Research, Ahmedabad, Opposite Air Force Station, Gandhinagar, Gujarat, 382355, India

    Akshay Srivastava

Authors
  1. Sagarkumar Patel
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  2. Anwesha Das
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  3. Payal Meshram
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  4. Ayushi Sharma
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  5. Arnab Chowdhury
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  6. Heena Jariyal
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  7. Aishika Datta
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  8. Deepaneeta Sarmah
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  9. Lakshmi Vineela Nalla
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  10. Bichismita Sahu
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  11. Amit Khairnar
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  12. Pallab Bhattacharya
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  13. Akshay Srivastava
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  14. Amit Shard
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Contributions

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.

Corresponding author

Correspondence to Amit Shard.

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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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