Neuronal migration is mediated by inositol hexakisphosphate kinase 1 via α-actinin and focal adhesion kinase

Chenglai Fu, Jing Xu, Weiwei Cheng, Tomas Rojas, Alfred C. Chin, Adele M Snowman, Maged Harraz, Solomon H Snyder

Research output: Contribution to journalArticle

Abstract

Inositol hexakisphosphate kinase 1 (IP6K1), which generates 5-diphosphoinositol pentakisphosphate (5-IP7), physiologically mediates numerous functions. We report that IP6K1 deletion leads to brain malformation and abnormalities of neuronal migration. IP6K1 physiologically associates with α-actinin and localizes to focal adhesions. IP6K1 deletion disrupts α-actinin's intracellular localization and function. The IP6K1 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 IP6K1 abolishes α-actinin tyrosine phosphorylation, which is known to be regulated by focal adhesion kinase (FAK). FAK phosphorylation is substantially decreased in IP6K1 deleted cells. 5-IP7, a product of IP6K1, promotes FAK autophosphorylation. Pharmacologic inhibition of IP6K by TNP [N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl)purine] recapitulates the phenotype of IP6K1 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.

Original languageEnglish (US)
Pages (from-to)2036-2041
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number8
DOIs
StatePublished - Feb 21 2017

Fingerprint

Actinin
Focal Adhesion Protein-Tyrosine Kinases
Phosphorylation
Stress Fibers
Focal Adhesions
Cell Movement
Tyrosine
inositol hexakisphosphate kinase
Phosphotransferases
Phenotype
Brain

Keywords

  • Actinin
  • Brain malformation
  • FAK
  • Inositol pyrophosphate
  • IP6K

ASJC Scopus subject areas

  • General

Cite this

Neuronal migration is mediated by inositol hexakisphosphate kinase 1 via α-actinin and focal adhesion kinase. / Fu, Chenglai; Xu, Jing; Cheng, Weiwei; Rojas, Tomas; Chin, Alfred C.; Snowman, Adele M; Harraz, Maged; Snyder, Solomon H.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 8, 21.02.2017, p. 2036-2041.

Research output: Contribution to journalArticle

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