Title | Neuronal migration is mediated by inositol hexakisphosphate kinase 1 via α-actinin and focal adhesion kinase. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Fu C, Xu J, Cheng W, Rojas T, Chin AC, Snowman AM, Harraz MM, Snyder SH |
Journal | Proc Natl Acad Sci U S A |
Volume | 114 |
Issue | 8 |
Pagination | 2036-2041 |
Date Published | 2017 02 21 |
ISSN | 1091-6490 |
Keywords | Actinin, Animals, Brain, Cell Line, Cell Movement, Enzyme Inhibitors, Focal Adhesion Kinase 1, Focal Adhesion Protein-Tyrosine Kinases, Humans, Inositol Phosphates, Mice, Mice, Knockout, Neurons, Phosphorylation, Phosphotransferases (Phosphate Group Acceptor), RNA Interference, RNA, Small Interfering |
Abstract | Inositol hexakisphosphate kinase 1 (IP6K1), which generates 5-diphosphoinositol pentakisphosphate (5-IP7), physiologically mediates numerous functions. We report that deletion leads to brain malformation and abnormalities of neuronal migration. IP6K1 physiologically associates with α-actinin and localizes to focal adhesions. deletion disrupts α-actinin's intracellular localization and function. The deleted cells display substantial decreases of stress fiber formation and impaired cell migration and spreading. Regulation of α-actinin by IP6K1 requires its kinase activity. Deletion of abolishes α-actinin tyrosine phosphorylation, which is known to be regulated by focal adhesion kinase (FAK). FAK phosphorylation is substantially decreased in deleted cells. 5-IP7, a product of IP6K1, promotes FAK autophosphorylation. Pharmacologic inhibition of IP6K by TNP [N2-(-Trifluorobenzyl), N6-(-nitrobenzyl)purine] recapitulates the phenotype of deletion. These findings establish that IP6K1 physiologically regulates neuronal migration by binding to α-actinin and influencing phosphorylation of both FAK and α-actinin through its product 5-IP7. |
DOI | 10.1073/pnas.1700165114 |
Alternate Journal | Proc. Natl. Acad. Sci. U.S.A. |
PubMed ID | 28154132 |
PubMed Central ID | PMC5338408 |
Grant List | P50 DA000266 / DA / NIDA NIH HHS / United States |
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