Cellular migration is an essential prerequisite for metastatic dissemination of cancer cells. The present 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 tumour cell lines, and during tumour progression in the metastatic tumour 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 tumour cells by two different mechanisms: 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 tumour cell migration place the enzyme among the potential targets of anti-metastatic therapy.
