Kinase Group PyK
Kinase Classification: Group PyK (Pyruvate Kinase)
One human isoform of pyruvate kinase, PKM2 has recently been shown to have protein kinase activities that may be linked to its role in cancer cell proliferation.
Evolution
Pyruvate Kinases are found in most eukaryotes, bacteria and archaeae, where they mediate the final step in glycolysis. Their protein fold is different to all other known protein kinases, but is related to other metabolic enzymes. Two PK genes are found in mammals, encoding four major isoforms: The M1 (muscle, heart, brain) and M2 (fetal, tumors) forms are from the PKM2 gene, while PKLR produces the liver (L) and red blood cell (R) forms.
Domain Structure
Most of PK is covered by the PK barrel domain, which encodes the catalytic region. This is flanked by an unannotated N-terminal region and a defined PK_C alpha/beta domain. The catalytic barrel domain is related to that of pyruvate phosphate dikinase and phophoenolpyruvate carboxylase, and phosphoenolpyruvate mutase (InterPro).
Function
PK mediates the final step of glycolysis, by phosphorylating ADP to ATP (the reverse of most kinases) while dephosphorylating PEP (phosphoenolpyruvate) to pyruvate. PKM is a key regulatory step in glycolysis (Wikipedia). PKM2 is a splice isoform of the PKM2 gene which is found in fetal tissues and re-expressed in many tumors. Tetrameric PKM is an active glycolysis enzyme, but in tumor cells, most PKM is in a dimeric form, inactive in glycolysis, and found in the nucleus. Here it appears to regulate gene expression and tumor proliferation. PKM2 was first shown to phosphorylate histone H1, possibly on lysine [1], and then on a histone-associated protein, prothymosin alpha [2]. PKM2-expressing tumor cells develop excess PEP, and radiolabelling of this PEP showed transfer of the phosphate to the catalytic histidine of phosphoglycerate mutase (PGAM1), though it is unlikely that PKM2 was the kinase, as the activity fractionated away from the PKM2 protein and was elevated after knockdown of PKM2 [3]. More recently, PKM2 was shown to phosphorylate STAT3 on its activatory tyrosine, Y702 and that the phosphate was derived from PEP. This activation of STAT3 drove expression of mek5, a proliferation regulator in the cell line used. PKM1 did not show protein kinase activity, and neither PKLR nor any non-human PKs have shown protein kinase activity. A possible functional link between STAT3 and PKM2 is also seen in the binding of PKM2 to PIAS3, ad SUMO-E3 ligase that was first named as an inhibitor of activated STAT3 [4].
References
- Ignacak J and Stachurska MB. The dual activity of pyruvate kinase type M2 from chromatin extracts of neoplastic cells. Comp Biochem Physiol B Biochem Mol Biol. 2003 Mar;134(3):425-33. DOI:10.1016/s1096-4959(02)00283-x |
- Díaz-Jullien C, Moreira D, Sarandeses CS, Covelo G, Barbeito P, and Freire M. The M2-type isoenzyme of pyruvate kinase phosphorylates prothymosin α in proliferating lymphocytes. Biochim Biophys Acta. 2011 Feb;1814(2):355-65. DOI:10.1016/j.bbapap.2010.10.004 |
- Vander Heiden MG, Locasale JW, Swanson KD, Sharfi H, Heffron GJ, Amador-Noguez D, Christofk HR, Wagner G, Rabinowitz JD, Asara JM, and Cantley LC. Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science. 2010 Sep 17;329(5998):1492-9. DOI:10.1126/science.1188015 |
- Spoden GA, Morandell D, Ehehalt D, Fiedler M, Jansen-Dürr P, Hermann M, and Zwerschke W. The SUMO-E3 ligase PIAS3 targets pyruvate kinase M2. J Cell Biochem. 2009 May 15;107(2):293-302. DOI:10.1002/jcb.22125 |
- Gao X, Wang H, Yang JJ, Liu X, and Liu ZR. Pyruvate kinase M2 regulates gene transcription by acting as a protein kinase. Mol Cell. 2012 Mar 9;45(5):598-609. DOI:10.1016/j.molcel.2012.01.001 |
