Neuronal migration is mediated by inositol hexakisphosphate kinase 1 via α-actinin and focal adhesion kinase.
Inositol hexakisphosphate kinase 1 (IP6K1), which generates 5-diphosphoinositol pentakisphosphate (5-IP7), physiologically mediates numerous functions. We report thatIP6K1deletion leads to brain malformation and abnormalities of neuronal migration. IP6K1 physiologically associates with α-actinin and localizes to focal adhesions.IP6K1deletion disrupts α-actinin's intracellular localization and function. TheIP6K1deleted 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 ofIP6K1abolishes α-actinin tyrosine phosphorylation, which is known to be regulated by focal adhesion kinase (FAK). FAK phosphorylation is substantially decreased inIP6K1deleted 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 ofIP6K1deletion. 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.
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Chenglai
0000-0003-4300-9948
C
Fu
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Jing
J
Xu
Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Weiwei
W
Cheng
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Tomas
T
Rojas
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Alfred C
AC
Chin
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Adele M
AM
Snowman
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Maged M
MM
Harraz
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205; ssnyder@jhmi.edu.|Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205.|Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Solomon H
SH
Snyder
D000185:Actinin / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000002:abnormalities / Q000201:enzymology; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology*; D010766:Phosphorylation; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism
D004791:Enzyme Inhibitors; C485444:Ihpk1 protein, mouse; D007295:Inositol Phosphates; D034741:RNA, Small Interfering; D000185:Actinin; C079849:1-diphosphoinositol pentakisphosphate; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; C496051:Ptk2 protein, mouse; D017856:Phosphotransferases (Phosphate Group Acceptor); C115134:IP6K1 protein, human
FAK; IP6K; actinin; brain malformation; inositol pyrophosphate