title: 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.
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.
authors.affiliation: Institut für Biochemie und Molekularbiologie I, Zelluläre Signaltransduktion, Universitätsklinikum Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany. s.windhorst@uke.uni-hamburg.de
authors.forename: Sabine
authors.initials: S
authors.lastname: Windhorst
authors.forename: Ralf
authors.initials: R
authors.lastname: Fliegert
authors.forename: Christine
authors.initials: C
authors.lastname: Blechner
authors.forename: Katharina
authors.initials: K
authors.lastname: Möllmann
authors.forename: Zara
authors.initials: Z
authors.lastname: Hosseini
authors.forename: Thomas
authors.initials: T
authors.lastname: Günther
authors.forename: Maike
authors.initials: M
authors.lastname: Eiben
authors.forename: Lydia
authors.initials: L
authors.lastname: Chang
authors.forename: Hong-Ying
authors.initials: HY
authors.lastname: Lin
authors.forename: Werner
authors.initials: W
authors.lastname: Fanick
authors.forename: Udo
authors.initials: U
authors.lastname: Schumacher
authors.forename: Burkhard
authors.initials: B
authors.lastname: Brandt
authors.forename: Georg W
authors.initials: GW
authors.lastname: Mayr
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002465:Cell Movement; D003599:Cytoskeleton / Q000378:metabolism / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000201:enzymology* / Q000473:pathology / Q000628:therapy; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014183:Transplantation, Heterologous
chemical_list: D000199:Actins; D007295:Inositol Phosphates; D009363:Neoplasm Proteins; C081655:inositol-1,3,4,5-tetrakisphosphate; D017853:Phosphotransferases (Alcohol Group Acceptor); C051038:Inositol 1,4,5-trisphosphate 3-kinase; D010744:Phosphoric Monoester Hydrolases; D002118:Calcium