Abstract
Phosphatase and tensin homologue (PTEN) is a dual lipid-protein phosphatase that catalyzes the conversion of phosphoinositol 3,4,5-triphosphate to phosphoinositol 4,5-bisphosphate and thereby inhibits PI3K-Akt-dependent cell proliferation, migration, and tumor vascularization. We have uncovered a previously unrecognized role for PTEN in regulating Ca(2+) entry through transient receptor potential canonical channel 6 (TRPC6) that does not require PTEN phosphatase activity. We show that PTEN tail-domain residues 394-403 permit PTEN to associate with TRPC6. The inflammatory mediator thrombin promotes this association. Deletion of PTEN residues 394-403 prevents TRPC6 cell surface expression and Ca(2+) entry. However, PTEN mutant, C124S, which lacks phosphatase activity, did not alter TRPC6 activity. Thrombin failed to increase endothelial monolayer permeability in the endothelial cells, transducing the Δ394-403 PTEN mutant. Paradoxically, we also show that thrombin failed to induce endothelial cell migration and tube formation in cells transducing the Δ394-403 PTEN mutant. Our results demonstrate that PTEN, through residues 394-403, serves as a scaffold for TRPC6, enabling cell surface expression of the channel. Ca(2+) entry through TRPC6 induces an increase in endothelial permeability and directly promotes angiogenesis. Thus, PTEN is indicated to play a role beyond suppressing PI3K signaling.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Amino Acid Sequence
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Calcium / metabolism*
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Capillary Permeability / drug effects
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Capillary Permeability / physiology*
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Cell Movement / drug effects
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Cell Movement / physiology
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Cell Proliferation / drug effects
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Cells, Cultured
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Endothelial Cells / cytology
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Endothelial Cells / metabolism*
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / physiology
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Hemostatics / metabolism
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Hemostatics / pharmacology
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Humans
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Inflammation Mediators / metabolism
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Inflammation Mediators / pharmacology
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Inositol Phosphates / genetics
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Inositol Phosphates / metabolism
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Mutation, Missense
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Neovascularization, Physiologic / drug effects
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Neovascularization, Physiologic / physiology*
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PTEN Phosphohydrolase / genetics
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PTEN Phosphohydrolase / metabolism*
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Protein Structure, Tertiary
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Sequence Deletion
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Signal Transduction / drug effects
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Signal Transduction / physiology
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TRPC Cation Channels / genetics
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TRPC Cation Channels / metabolism*
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TRPC6 Cation Channel
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Thrombin / metabolism
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Thrombin / pharmacology
Substances
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Hemostatics
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Inflammation Mediators
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Inositol Phosphates
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TRPC Cation Channels
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TRPC6 Cation Channel
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TRPC6 protein, human
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inositol 3,4,5-trisphosphate
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inositol 4,5-bisphosphate
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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PTEN Phosphohydrolase
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PTEN protein, human
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Thrombin
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Calcium