Abstract
Dysfunction of the tubby protein results in maturity-onset obesity in mice. Tubby has been implicated as a transcription regulator, but details of the molecular mechanism underlying its function remain unclear. Here we show that tubby functions in signal transduction from heterotrimeric GTP-binding protein (G protein)-coupled receptors. Tubby localizes to the plasma membrane by binding phosphatidylinositol 4,5-bisphosphate through its carboxyl terminal "tubby domain." X-ray crystallography reveals the atomic-level basis of this interaction and implicates tubby domains as phosphorylated-phosphatidyl- inositol binding factors. Receptor-mediated activation of G protein alphaq (Galphaq) releases tubby from the plasma membrane through the action of phospholipase C-beta, triggering translocation of tubby to the cell nucleus. The localization of tubby-like protein 3 (TULP3) is similarly regulated. These data suggest that tubby proteins function as membrane-bound transcription regulators that translocate to the nucleus in response to phosphoinositide hydrolysis, providing a direct link between G-protein signaling and the regulation of gene expression.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Active Transport, Cell Nucleus
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Adaptor Proteins, Signal Transducing
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Amino Acid Sequence
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Animals
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Cell Membrane / metabolism
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Cell Nucleus / metabolism*
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Cells, Cultured
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Crystallography, X-Ray
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GTP-Binding Protein alpha Subunits, Gq-G11
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Gene Expression Regulation
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Heterotrimeric GTP-Binding Proteins / metabolism*
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Humans
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Intercellular Signaling Peptides and Proteins
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Intracellular Signaling Peptides and Proteins
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Isoenzymes / metabolism*
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Membrane Lipids / metabolism
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Mice
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Models, Biological
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Molecular Sequence Data
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Nuclear Localization Signals
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Obesity / genetics
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Obesity / metabolism
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Phosphatidylinositol 4,5-Diphosphate / metabolism*
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Phosphatidylinositol Phosphates / metabolism
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Phospholipase C beta
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Phosphorylation
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Protein Structure, Tertiary
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Proteins / chemistry
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Proteins / genetics
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Proteins / metabolism*
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Receptor, Serotonin, 5-HT2C
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Receptors, Muscarinic / metabolism
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Receptors, Serotonin / metabolism
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Recombinant Fusion Proteins / metabolism
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Signal Transduction*
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Transcription Factors / chemistry
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Type C Phospholipases / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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Intercellular Signaling Peptides and Proteins
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Intracellular Signaling Peptides and Proteins
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Isoenzymes
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Membrane Lipids
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Nuclear Localization Signals
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Phosphatidylinositol 4,5-Diphosphate
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Phosphatidylinositol Phosphates
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Proteins
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Receptor, Serotonin, 5-HT2C
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Receptors, Muscarinic
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Receptors, Serotonin
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Recombinant Fusion Proteins
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TULP3 protein, human
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Transcription Factors
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Tub protein, mouse
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Tulp3 protein, mouse
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Type C Phospholipases
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Phospholipase C beta
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GTP-Binding Protein alpha Subunits, Gq-G11
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Heterotrimeric GTP-Binding Proteins