Table 1:

Post-translational modifications of PKM2 and their disease-associated physiological relevance.

Modification	Specific site	Stimuli/ Source	Regulators	Effects	Proposed Function	Reference
Phosphorylation	S-202	IGF-1	AKT1	Promotes nuclear translocation	Nuclear PKM2 interacts with STAT5 to induce cellular proliferation	[62]
	S-37	EGF	ERK1/2		Nuclear PKM2 induces C-Myc expression to upregulate GLUT1, LADH, and PTB expression	[32]
	T-454		PIM2	Increases PKM2 protein stability Reduces PKM2 enzymatic activity	Promotes PKM2 co-activator activity on HIF-1α and β-catenin Lowers mitochondrial respiration Promotes cancer cell proliferation	[206]
	T-328		GSK-3β HSP90		Increases glycolysis Lowers the apoptotic rate Promotes tumor growth	[55]
	Y-105	bFGF	FGFR1 ABL JAK2 FLT3	Inhibits the formation of the active tetramer Decreases PKM2 enzymatic activity	Increases cancer cell proliferation, lactate production, and decreases oxidative phosphorylation	[54]
De-phosphorylation	Y-105	Insulin	PTP1B	Increases PKM2 enzymatic activity	Contributes to glycemic control	[207]
	Y	Morin (LMW- PTP inhibitor)	LMW-PTP	Inhibits PKM2 nuclear translocation Increases PKM2 enzymatic activity	Reduces glycolysis and enhances oxidative metabolism	[63]
SUMOylation	K-336		SUMO1	Increases PKM2 protein stability	Promotes glycolysis Promotes PKM2 cofactor functions Promotes cancer cells proliferation	[208]
Acetylation	K-305	Trichostatin A (HDAC I & II inhibitor) Nicotinamide Glucose	PCAF	Reduces PKM2 enzymatic activity Promotes PKM2 degradation	Promotes glycolysis Promotes cellular proliferation and tumorigenesis	[52]
	K-433	Trichostatin A Nicotinamide	p300 acetyltransferase	Reduces PKM2 enzymatic activity Promotes PKM2 nuclear translocation and kinase activity	Promotes cell proliferation and tumorigenesis	[51]
Deacetylation	K-433	Starvation	SIRT6	Increases PKM2 nuclear export Reduces PKM2 cofactor function	Reduces cancer cell proliferation and invasiveness	[64]
Oxidation	C-358	Diamide H2O2	ROS	Promotes the dissociation of the tetramer form to reduce PKM2 enzymatic activity	Lowers ROS production Enhances tumor growth	[50]
		Glucose		Reduces PKM2 enzymatic activity	Contributes to DN pathogenesis	[204]
Hydroxylation	P-403 P-408		PHD3	Promotes PKM2 nuclear translocation Promotes HIF-1α transcriptional activity	Promotes the Warburg effect Increases lactate production	[66]
S-nitrosylation	C-423 C-424	NO	AKR1A1 (negative regulator)	Inhibits PKM2 tetramer formation	Increases glycolytic metabolites accumulation Promotes antioxidants defense Protects against AKI	[58]
	C-358		eNOS	Reduces PKM2 enzymatic activity Delays atherosclerosis development	Amplifies the antioxidants defense	[59]
Methylation	R-445 R-447	S-Adenosyl-methionine	CARM1 PRMT6	Promotes PKM2 tetramer formation to increase PKM2 enzymatic activity	Reduces cellular proliferation	[65]
	R-445 R-447 R-455	S-Adenosyl-methionine	CARM1	Has little effect on PKM2 enzymatic activity Decreases InsP3R1 & InsP3R3 expression	Promotes breast cancer cells proliferation Reduces mitochondrial respiration	[53]
Succinylation	K-498	Suramin (SIRT5 inhibitor)	SIRT5 (negative regulator)	Increases PKM2 activity	Reduces NADPH generation Lowers cellular proliferation and tumor growth	[60]
Succinylation	K-311	succinyl-CoA	SIRT5 (negative regulator)	Decreases PKM2 enzymatic activity Promotes PKM2 nuclear translocation Promotes PKM2 kinase activity	Promotes pro-inflammatory cytokines Increases the susceptibility to colitis	[172]