Abstract
The inositol pyrophosphates, molecular messengers containing an energetic pyrophosphate bond, impact a wide range of biologic processes. They are generated primarily by a family of three inositol hexakisphosphate kinases (IP6Ks), the principal product of which is diphosphoinositol pentakisphosphate (IP7). We report that IP6K2, via IP7 synthesis, is a major mediator of cancer cell migration and tumor metastasis in cell culture and in intact mice. IP6K2 acts by enhancing cell-matrix adhesion and decreasing cell-cell adhesion. This action is mediated by IP7-elicited nuclear sequestration and inactivation of the tumor suppressor liver kinase B1 (LKB1). Accordingly, inhibitors of IP6K2 offer promise in cancer therapy.
Keywords:
IP6K; LKB1; cell-matrix adhesion; cell–cell adhesion; metastasis.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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AMP-Activated Protein Kinases
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Animals
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Blotting, Western
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Cell Adhesion / drug effects*
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Cell Adhesion / physiology
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Cell Line, Tumor
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Cell Movement / drug effects*
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Extracellular Matrix / metabolism
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Humans
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Immunoprecipitation
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Inositol Phosphates / biosynthesis
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Inositol Phosphates / metabolism*
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Mice
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Mice, Nude
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Microscopy, Fluorescence
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Neoplasm Metastasis / physiopathology*
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Phosphotransferases (Phosphate Group Acceptor) / metabolism
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Phosphotransferases (Phosphate Group Acceptor) / pharmacology*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
Substances
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Inositol Phosphates
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1-diphosphoinositol pentakisphosphate
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Protein Serine-Threonine Kinases
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Stk11 protein, mouse
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AMP-Activated Protein Kinases
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Phosphotransferases (Phosphate Group Acceptor)
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inositol hexakisphosphate kinase