IKAP localizes to membrane ruffles with filamin A and regulates actin cytoskeleton organization and cell migration.

Loss-of-function mutations in the IKBKAP gene, which encodes IKAP (ELP1), cause familial dysautonomia (FD), with defective neuronal development and maintenance. Molecular mechanisms leading to FD are poorly understood. We demonstrate that various RNA-interference-based depletions of IKAP lead to defective adhesion and migration in several cell types, including rat primary neurons. The defects could be rescued by reintroduction of wild-type IKAP but not by FD-IKAP, a truncated form of IKAP constructed according to the mutation found in the majority of FD patients. Cytosolic IKAP co-purified with proteins involved in cell migration, including filamin A, which is also involved in neuronal migration. Immunostaining of IKAP and filamin A revealed a distinct co-localization of these two proteins in membrane ruffles. Depletion of IKAP resulted in a significant decrease in filamin A localization in membrane ruffles and defective actin cytoskeleton organization, which both could be rescued by the expression of wild-type IKAP but not by FD-IKAP. No downregulation in the protein levels of paxillin or beclin 1, which were recently described as specific transcriptional targets of IKAP, was detected. These results provide evidence for the role of the cytosolic interactions of IKAP in cell adhesion and migration, and support the notion that cell-motility deficiencies could contribute to FD.

Citation

Lars Dan Johansen, Tiina Naumanen, Astrid Knudsen, Nina Westerlund, Irina Gromova, Melissa Junttila, Christina Nielsen, Trine Bøttzauw, Aviva Tolkovsky, Jukka Westermarck, Eleanor T Coffey, Marja Jäättelä, Tuula Kallunki. IKAP localizes to membrane ruffles with filamin A and regulates actin cytoskeleton organization and cell migration. Journal of cell science. 2008 Mar 15;121(Pt 6):854-64

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PMID: 18303054

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