Forschungs- & Entwicklungsinformationsdienst der Gemeinschaft - CORDIS

Final Activity Report Summary - PIPKIGKO (Targeted disruption of the type I phospatidylinositol phosphate kinase gamma gene and the effect on focal adhesion formation in a mouse genetic background)

Focal adhesions are sites of cell-extracellular matrix contact. The formation of such adhesions is thought to be mediated in part by the binding of specific focal adhesion proteins to an acidic phospholipid, phosphatidylinositol-4,5-bisphosphate (PIP2). Local production of PIP2 is likely accomplished by a lipid kinase, PIP kinase Type I gamma, which is found in focal adhesions. The prevailing hypothesis is that disruption of local PIP2 production will impair the formation, dynamics or disassembly of focal adhesions. To test this hypothesis, the focal adhesion targeting sequence of the PIP kinase Type I gamma gene was deleted in mice, and the consequences of this deletion were studied in both mice and cells.

Surprisingly, mouse development was unaffected when the targeting of PIP kinase to focal adhesions was abrogated. Mice were viable, fertile and had a normal lifespan. Cells isolated from PIP kinase knockout mice showed no defect in adhesion to extracellular matrix, migration, proliferation or signalling pathways located downstream of focal adhesions, but early stages of spreading of PIP kinase -/- cells on fibronectin were delayed compared to genetically unaltered cells. Therefore we conclude that previous in vitro studies which suggest that local production of PIP2 at focal adhesions is important for focal adhesion integrity overemphasize the importance of PIP kinase Type I gamma, since the effect of its deletion are minor at best.

However, a closer analysis of PIP kinase -/- mice has revealed a reduction in storage iron content in the spleen and liver, consistent with a defect in iron metabolism in these mice. This finding complements two recent studies which uncover a role for PIP kinase Type I gamma in clathrin-mediated endocytosis, the main route for iron uptake by cells. This finding is currently being examined in closer detail in cells as well as in mice by restricting their source of dietary iron.

In summary, this project has revealed a greater in vivo role for PIP kinase Type I gamma in endocytosis in general, and iron homeostasis in particular, rather than in cell adhesion as previously thought.

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