PKM2 phosphorylates MLC2 and regulates cytokinesis of tumour cells

Nat Commun. 2014 Nov 21:5:5566. doi: 10.1038/ncomms6566.

Abstract

Pyruvate kinase M2 (PKM2) is expressed at high levels during embryonic development and tumour progression and is important for cell growth. However, it is not known whether it directly controls cell division. Here, we found that Aurora B phosphorylates PKM2, but not PKM1, at T45; this phosphorylation is required for PKM2's localization and interaction with myosin light chain 2 (MLC2) in the contractile ring region of mitotic cells during cytokinesis. PKM2 phosphorylates MLC2 at Y118, which primes the binding of ROCK2 to MLC2 and subsequent ROCK2-dependent MLC2 S15 phosphorylation. PKM2-regulated MLC2 phosphorylation, which is greatly enhanced by EGF stimulation or EGFRvIII, K-Ras G12V and B-Raf V600E mutant expression, plays a pivotal role in cytokinesis, cell proliferation and brain tumour development. These findings underscore the instrumental function of PKM2 in oncogenic EGFR-, K-Ras- and B-Raf-regulated cytokinesis and tumorigenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / pharmacology
  • Animals
  • Aurora Kinase B / metabolism*
  • Brain Neoplasms / genetics
  • Cardiac Myosins / genetics
  • Cardiac Myosins / metabolism*
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Cycle / genetics
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Cell Transformation, Neoplastic / genetics
  • Cytokinesis / physiology*
  • ErbB Receptors / metabolism
  • Gene Expression Regulation, Neoplastic
  • HCT116 Cells
  • Humans
  • Leupeptins / pharmacology
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Nude
  • Mitosis / physiology
  • Myosin Light Chains / genetics
  • Myosin Light Chains / metabolism*
  • Phosphorylation
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins B-raf / metabolism
  • Proto-Oncogene Proteins p21(ras)
  • Pyridines / pharmacology
  • Pyruvate Kinase / antagonists & inhibitors
  • Pyruvate Kinase / genetics
  • Pyruvate Kinase / metabolism*
  • RNA Interference
  • RNA, Small Interfering
  • Thyroid Hormone-Binding Proteins
  • Thyroid Hormones / genetics
  • Thyroid Hormones / metabolism*
  • ras Proteins / metabolism
  • rho-Associated Kinases / antagonists & inhibitors
  • rho-Associated Kinases / metabolism

Substances

  • Amides
  • Carrier Proteins
  • KRAS protein, human
  • Leupeptins
  • Membrane Proteins
  • Myosin Light Chains
  • Proto-Oncogene Proteins
  • Pyridines
  • RNA, Small Interfering
  • Thyroid Hormones
  • myosin light chain 2
  • Y 27632
  • Pyruvate Kinase
  • EGFR protein, human
  • ErbB Receptors
  • AURKB protein, human
  • Aurora Kinase B
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • ROCK2 protein, human
  • rho-Associated Kinases
  • Cardiac Myosins
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde