Tubby proteins: the plot thickens

Carroll, Kilpatrick; Gómez, Carlos A.; Shapiro, Lawrence

doi:10.1038/nrm1278

Cited by 102 publications

(74 citation statements)

References 49 publications

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“…5). For example, deletion of the Tub gene, which is a T 3 -regulated, phosphoinositide-binding, transcription factor in the brain (35), produces many of the same effects on the developing sensory nervous system as removing thyroid hormone (3). Both the human tubby protein H-tulp-1 (amino acids 296-347) and the human KCNH2 channel protein H-erg-1 (amino acids 12-62) contain homologous phosphoinositidebinding domains, which could target them to a signaling complex surrounding PI3K at the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

Rapid signaling at the plasma membrane by a nuclear receptor for thyroid hormone

Storey

Gentile

Ullah

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

109

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Many nuclear hormones have physiological effects that are too rapid to be explained by changes in gene expression and are often attributed to unidentified or novel G protein-coupled receptors. Thyroid hormone is essential for normal human brain development, but the molecular mechanisms responsible for its effects remain to be identified. Here, we present direct molecular evidence for potassium channel stimulation in a rat pituitary cell line (GH 4C1) by a nuclear receptor for thyroid hormone, TR␤, acting rapidly at the plasma membrane through phosphatidylinositol 3-kinase (PI3K) to slow the deactivation of KCNH2 channels already in the membrane. Signaling was disrupted by heterologous expression of TR␤ receptors with mutations in the ligand-binding domain that are associated with neurological disorders in humans, but not by mutations that disrupt DNA binding. More importantly, PI3K-dependent signaling was reconstituted in cell-free patches of membrane from CHO cells by heterologous expression of human KCNH2 channels and TR␤, but not TR␣, receptors. TR␤ signaling through PI3K provides a molecular explanation for the essential role of thyroid hormone in human brain development and adult lipid metabolism.neuronal development ͉ phosphatidylinositol 3-kinase ͉ potassium channels ͉ Rac ͉ KCNH2 T he thyroid hormone, L-3,5,3Јtriiodothyronine (T 3 ), plays an essential role in the development and metabolism of many tissues and organs (1). In particular, mammalian brain development is disrupted when T 3 signaling is reduced by inherited mutations in the T 3 receptor gene, THR␤, or when the synthesis or transport of the T 3 prohormone thyroxine (tetraiodothyronine) is reduced by dietary iodine deficiency or environmental toxicants (2-4). T 3 also regulates its own circulating levels through negative feedback on pituitary thyrotropes, which secrete thyroid stimulating hormone (1). Two genes, THR␣ and THR␤, encode four alternately spliced ligand-binding zincfinger receptor proteins from the c-erbA family, which mediate T 3 actions on gene expression (5), but specific T 3 -regulated genes involved directly in neural development remain to be identified. Recently, however, attention has shifted to the rapid, nongenomic signaling by T 3 (6) and other thyroxine metabolites (7).For example, we previously reported a Rac-dependent effect of T 3 on voltage-activated potassium channels encoded by the ether-a-go-go-related gene KCNH2 in a rat pituitary cell line (8). KCNH2 proteins are voltage-activated potassium channels that regulate spike frequency in electrically excitable cells, such as the endocrine cells of the pituitary, through their unique kinetics of inactivation and recovery (9). Because they inactivate almost immediately after activation at positive voltages during the peak of each spike, and then reactivate before closing when the membrane repolarizes after the spike, they contribute to determining the interspike interval. Thus, increasing KCNH2 activity decreases excitability and secretion. Rapid effects of thyroid hormo...

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Section: Discussionmentioning

confidence: 99%

Rapid signaling at the plasma membrane by a nuclear receptor for thyroid hormone

Storey

Gentile

Ullah

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

109

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“…The gene tub-1 is the worm ortholog of murine tubby which, when mutated, leads to neuronal deficits and late-onset obesity (Carroll et al, 2004). tub-1 mutant worms exhibit functional defects in CSN and show a mild elevation of lipid accumulation (H.Y.M., unpublished data).…”

Section: Expression Analysis Of the Xbx Gene Candidatesmentioning

confidence: 99%

Analysis of xbx genes in C. elegans

et al. 2005

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Cilia and flagella are widespread eukaryotic subcellular components that are conserved from green algae to mammals. In different organisms they function in cell motility, movement of extracellular fluids and sensory reception. While the function and structural description of cilia and flagella are well established, there are many questions that remain unanswered. In particular, very little is known about the developmental mechanisms by which cilia are generated and shaped and how their components are assembled into functional machineries. To find genes involved in cilia development we used as a search tool a promoter motif, the X-box, which participates in the regulation of certain ciliary genes in the nematode Caenorhabditis elegans.By using a genome search approach for X-box promoter motif-containing genes (xbx genes) we identified a list of about 750 xbx genes (candidates). This list comprises some already known ciliary genes as well as new genes, many of which we hypothesize to be important for cilium structure and function. We derived a C. elegans X-box consensus sequence by in vivo expression analysis. We found that xbx gene expression patterns were dependent on particular Xbox nucleotide compositions and the distance from the respective gene start. We propose a model where DAF-19, the RFX-type transcription factor binding to the X-box, is responsible for the development of a ciliary module in C. elegans, which includes genes for cilium structure, transport machinery, receptors and other factors.

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“…PI binding domains include pleckstrin homology (PH) (13)(14)(15), Fab1, YOTB, Vac1, and EEA1 (FYVE) (16,17), Phox (PX) (18,19), Epsin N-Terminal Homology (ENTH) (20 -22), AP180 N-Terminal Homology (ANTH) (20 -22), Bin Amphiphysin Rvs (BAR) (22)(23)(24)(25), Band 4.1, Ezrin, Radixin, Moesin (FERM) (26), Tubby (27), and protein kinase C Conserved 2 (C2) (28 -31) domains.…”

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confidence: 99%

Mechanistic Basis of Differential Cellular Responses of Phosphatidylinositol 3,4-Bisphosphate- and Phosphatidylinositol 3,4,5-Trisphosphate-binding Pleckstrin Homology Domains

Manna

Albanese

Park

et al. 2007

Journal of Biological Chemistry

127

150

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Phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P 2 ) and phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P 3 ) are lipid second messengers that regulate various cellular processes by recruiting a wide range of downstream effector proteins to membranes. Several pleckstrin homology (PH) domains have been reported to interact with PtdIns(3,4)P 2 and PtdIns(3,4,5)P 3 . To understand how these PH domains differentially respond to PtdIns(3,4)P 2 and PtdIns(3,4,5)P 3 signals, we quantitatively determined the PtdIns(3,4)P 2 and PtdIns(3,4,5)P 3 binding properties of several PH domains, including Akt, ARNO, Btk, DAPP1, Grp1, and C-terminal TAPP1 PH domains by surface plasmon resonance and monolayer penetration analyses. The measurements revealed that these PH domains have significant different phosphoinositide specificities and affinities. Btk-PH and TAPP1-PH showed genuine PtdIns(3,4,5)P 3 and PtdIns(3,4)P 2 specificities, respectively, whereas other PH domains exhibited less pronounced specificities. Also, the PH domains showed different degrees of membrane penetration, which greatly affected the kinetics of their membrane dissociation. Mutational studies showed that the presence of two proximal hydrophobic residues on the membrane-binding surface of the PH domain is important for membrane penetration and sustained membrane residence. When NIH 3T3 cells were stimulated with platelet-derived growth factor to generate PtdIns(3,4,5)P 3 , reversible translocation of Btk-PH, Grp1-PH, ARNO-PH, DAPP1-PH, and its L177A mutant to the plasma membrane was consistent with their in vitro membrane binding properties. Collectively, these studies provide new insight into how various PH domains would differentially respond to cellular PtdIns(3,4)P 2 and PtdIns(3,4,5)P 3 signals. Phosphoinositides (PIs)2 are mono-and polyphosphorylated derivatives of phosphatidylinositol (PtdIns) (1-3). AlthoughPIs are minor components of membrane lipids, they regulate a wide range of biological processes, including cell proliferation, cell survival, differentiation, signal transduction, cytoskeleton organization, and membrane trafficking (1-3). PIs regulate these cellular processes primarily by serving as site-specific membrane signals that mediate the membrane recruitment and regulation of effector proteins. The PI-mediated cellular processes allow exceptional spatiotemporal specificity because the spatial and temporal distribution of various PIs is dynamically and tightly regulated by a series of PI-modifying enzymes, such as phospholipases, lipid kinases, and lipid phosphatases, located in different cell membranes (1-3). For instance, phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P 2 ) and phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P 3 ) are mainly found in the plasma membrane, whereas phosphatidylinositol 3-phosphate (PtdIns3P), phosphatidylinositol 4-phosphate (PtdIns4P), phosphatidylinositol 5-phosphate (PtdIns5P), and phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P 2 ) are primarily present in endosomes, Golgi, nucl...

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Tubby proteins: the plot thickens

Cited by 102 publications

References 49 publications

Rapid signaling at the plasma membrane by a nuclear receptor for thyroid hormone

Rapid signaling at the plasma membrane by a nuclear receptor for thyroid hormone

Analysis of xbx genes in C. elegans

Mechanistic Basis of Differential Cellular Responses of Phosphatidylinositol 3,4-Bisphosphate- and Phosphatidylinositol 3,4,5-Trisphosphate-binding Pleckstrin Homology Domains

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