Inositol 1,4,5-trisphosphate 3-kinase A overexpression induces cytoskeletal re-organization and increases migration via a kinase-independent mechanism

Sabine Windhorst (1) , Christine Blechner , Hong-Ying Lin , Christian Elling , Marcus Nalaskowski , Tanja Kirchberger , Andreas H Guse , Georg W Mayr

1 Institut für Biochemie und Molekularbiologie I

In this study effects of increased inositol 1,4,5-trisphosphate 3-kinases-A (IP3K-A) expression were analyzed. H1299 cells overexpressing IP3K-A formed branching protrusions and under three-dimensional culture conditions they ex-hibited a motile fibroblast-like morphology. They lost the ability to form actin stress fibers and showed increased invasive migration in vitro. Furthermore, ex-pression levels of the mesenchymal marker proteins vimentin and N-cadherin were increased. The enzymatic function of IP3K-A is to phosphorylate the cal-cium mobilizing second messenger D-myo-inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) to D-myo-inositol 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P4). Accord-ingly, cells overexpressing IP3K-A showed reduced calcium release and altered concentrations of inositol phosphates, with decreasing concentrations of Ins(1,4,5)P3, inositol hexakisphosphate and inositol 1,2,3,4,5 pentakisphosphate, and increasing concentrations of Ins(1,3,4,5)P4. However, IP3K-A induced effects on cell morphology do not seem to be dependent on enzyme activity since a pro-tein devoid of enzyme activity also induced formation of branching protrusions. Therefore, we propose that the morphological changes induced by IP3K-A are mediated by non-enzymatic activities of the protein.

Mots clés: Life Sciences

Sabine Windhorst, Christine Blechner, Hong-Ying Lin, Christian Elling, Marcus Nalaskowski, et al.. Inositol 1,4,5-trisphosphate 3-kinase A overexpression induces cytoskeletal re-organization and increases migration via a kinase-independent mechanism. Biochemical Journal, 2008, 414 (3), pp.407-417. ⟨10.1042/BJ20080630⟩. ⟨hal-00479001⟩