Inositol 1,4,5-trisphosphate 3-kinase-A is a new cell motility-promoting protein that increases the metastatic potential of tumor cells by two functional activities

J Biol Chem. 2010 Feb 19;285(8):5541-54. doi: 10.1074/jbc.M109.047050. Epub 2009 Dec 17.


Cellular migration is an essential prerequisite for metastatic dissemination of cancer cells. This study demonstrates that the neuron/testis-specific F-actin-targeted inositol 1,4,5-trisphosphate 3-kinase-A (ITPKA) is ectopically expressed in different human tumor cell lines and during tumor progression in the metastatic tumor model Balb-neuT. High expression of ITPKA increases invasive migration in vitro and metastasis in a xenograft SCID mouse model. Mechanistic studies show that ITPKA promotes migration of tumor cells by two different mechanisms as follows: growth factor independently high levels of ITPKA induce the formation of large cellular protrusions by directly modulating the actin cytoskeleton. The F-actin binding activity of ITPKA stabilizes and bundles actin filaments and thus increases the levels of cellular F-actin. In growth factor-stimulated cells, the catalytically active domain enhances basal ITPKA-induced migration by activating store-operated calcium entry through production of inositol 1,3,4,5-tetrakisphosphate and subsequent inhibition of inositol phosphate 5-phosphatase. These two functional activities of ITPKA stimulating tumor cell migration place the enzyme among the potential targets of anti-metastatic therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Cytoskeleton / metabolism
  • Actins / metabolism
  • Animals
  • Calcium / metabolism
  • Cell Movement*
  • Cytoskeleton / metabolism
  • Cytoskeleton / pathology
  • Gene Expression Regulation, Enzymologic*
  • Gene Expression Regulation, Neoplastic*
  • Hep G2 Cells
  • Humans
  • Inositol Phosphates / metabolism
  • Mice
  • Mice, SCID
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / metabolism*
  • Neoplasm Transplantation
  • Neoplasms, Experimental / enzymology*
  • Neoplasms, Experimental / pathology
  • Neoplasms, Experimental / therapy
  • Phosphoric Monoester Hydrolases / metabolism
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Transplantation, Heterologous


  • Actins
  • Inositol Phosphates
  • Neoplasm Proteins
  • inositol-1,3,4,5-tetrakisphosphate
  • Phosphotransferases (Alcohol Group Acceptor)
  • Inositol 1,4,5-trisphosphate 3-kinase
  • Phosphoric Monoester Hydrolases
  • Calcium