Abstract |
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.
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Authors | Sabine Windhorst, Ralf Fliegert, Christine Blechner, Katharina Möllmann, Zara Hosseini, Thomas Günther, Maike Eiben, Lydia Chang, Hong-Ying Lin, Werner Fanick, Udo Schumacher, Burkhard Brandt, Georg W Mayr |
Journal | The Journal of biological chemistry
(J Biol Chem)
Vol. 285
Issue 8
Pg. 5541-54
(Feb 19 2010)
ISSN: 1083-351X [Electronic] United States |
PMID | 20022963
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- 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
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Topics |
- Actin Cytoskeleton
(metabolism)
- Actins
(metabolism)
- Animals
- Calcium
(metabolism)
- Cell Movement
- Cytoskeleton
(metabolism, 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, metabolism)
- Neoplasm Transplantation
- Neoplasms, Experimental
(enzymology, pathology, therapy)
- Phosphoric Monoester Hydrolases
(metabolism)
- Phosphotransferases (Alcohol Group Acceptor)
(antagonists & inhibitors, metabolism)
- Transplantation, Heterologous
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