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.

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 is ectopically expressed in different human tumor cell lines and during tumor progression in the metastatic tumor model Balb-neuT. High expression of increases invasive migration in vitro and metastasis in a xenograft SCID mouse model. Mechanistic studies show that ITduanyu1529 promotes migration of tumor cells by two different mechanisms as follows: growth factor independently high levels of ITduanyu1529 induce the formation of large cellular protrusions by directly modulating the actin cytoskeleton. The F-actin binding activity of ITduanyu1529 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 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 ITduanyu1529 stimulating tumor cell migration place the enzyme among the potential targets of anti-metastatic therapy.

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