The tubby family proteins
© BioMed Central Ltd 2011
Published: 28 June 2011
The tubby mouse shows a tripartite syndrome characterized by maturity-onset obesity, blindness and deafness. The causative gene Tub is the founding member of a family of related proteins present throughout the animal and plant kingdoms, each characterized by a signature carboxy-terminal tubby domain. This domain consists of a β barrel enclosing a central α helix and binds selectively to specific membrane phosphoinositides. The vertebrate family of tubby-like proteins (TULPs) includes the founding member TUB and the related TULPs, TULP1 to TULP4. Tulp1 is expressed in the retina and mutations in TULP1 cause retinitis pigmentosa in humans; Tulp3 is expressed ubiquitously in the mouse embryo and is important in sonic hedgehog (Shh)-mediated dorso-ventral patterning of the spinal cord. The amino terminus of these proteins is diverse and directs distinct functions. In the best-characterized example, the TULP3 amino terminus binds to the IFT-A complex, a complex important in intraflagellar transport in the primary cilia, through a short conserved domain. Thus, the tubby family proteins seem to serve as bipartite bridges through their phosphoinositide-binding tubby and unique amino-terminal functional domains, coordinating multiple signaling pathways, including ciliary G-protein-coupled receptor trafficking and Shh signaling. Molecular studies on this functionally diverse protein family are beginning to provide us with remarkable insights into the tubby-mouse syndrome and other related diseases.
Gene organization and evolutionary history
Monogenic diabetes-obesity syndromes in mice have been historically important in the discovery of genes important in their pathogenesis. The tubby mouse was initially identified as a spontaneous maturity-onset obesity syndrome in inbred backgrounds maintained at the Jackson Laboratory . The mice were later found to be deficient in hearing and vision . Positional cloning strategies by two groups mapped the causative mutation to a novel gene of unknown function called Tub [3, 4]. Subsequent studies identified a family of related proteins, present throughout the animal and plant kingdoms, each possessing a signature carboxy-terminal tubby domain capable of highly selective binding to specific phosphoinositides [5, 6]. The amino terminus of these proteins is varied and imparts diverse functions to them.
Phylogenetic analysis of the tubby family proteins suggests that the ecdysozoan TUB homologs, such as Drosophila TULP and Caenorhabditis elegans TUB-1, although related to the mammalian group of TULPs, might not be orthologs of a specific mammalian TULP  (Figure 1a). However, the C. elegans tub-1 regulates fat storage similarly to the mouse Tub, suggesting remarkable conservation in the fat storage pathways between invertebrates and vertebrates [18, 19]. TULP4, the distantly related TULP family member, is characterized by a large amino terminus containing WD repeats and E3 ubiquitin ligase binding motifs . TULP4 is also conserved in evolution, the Drosophila TUSP (tubby domain superfamily protein) and C. elegans TUB-2 being related homologs  (Figure 1a). The mammalian TULP4 is also distantly related to the intraflagellar transport complex A (IFT-A) protein subunit WDR35 (Figure 1a).
The tubby-like family of proteins is more extensive in plants, arising predominantly from segmental duplication events. This family is distinct from the mammalian cluster of tubby-like proteins and comprises 11 and 14 members in Arabidopsis and rice, respectively [20, 21] (Figure 1a). Most of these proteins have an amino-terminal F-box domain, which may function as a binding motif for specific E3 ubiquitin cullin family ligases. The Chlamydomonas tubby homolog TLP2 is also not closely related to any of the mammalian tubby-family proteins and was found to be highly upregulated in a genome-wide transcriptional analysis during flagellar regeneration in the green algae .
The tubby family proteins are related to the phospholipid scramblase family (PLSCRs). This was deduced from crystallography studies on the Arabidopsis protein At5g01750, a member of the DUF567 family . This Arabidopsis protein is related to PLSCRs and bears strong structural similarity to the prototypical tubby domain. PLSCRs are a family of cytoplasmic membrane-associated proteins linked by palmitoylation (as opposed to phosphoinositide binding in the case of the tubby family) and mediate flippase activity, the trans-bilayer exchange of membrane phospholipids . The tubby family is found only in eukaryotes, whereas the scramblase/DUF567 family is found in eukaryotes and eubacteria, suggesting that the tubby family of proteins evolved from an ancestral scramblase-like protein.
Characteristic structural features
The amino termini of these proteins are diverse and direct distinct functions. For example, a conserved domain in the amino terminus enables some members of the tubby family (TULP3, TULP2 and TUB but not TULP1 and TULP4) to bind to ciliary IFT-A  (Figures 1b and 2c). This unexpected insight came from tandem affinity purification and mass spectrometry analysis of tubby family interacting proteins. Primary cilia are microtubule-based cellular antennae acting as sensory signaling compartments in processes ranging from mammalian sonic hedgehog (Shh) signaling to neuronal control of obesity. Intraflagellar transport is an ancient, conserved mechanism required to assemble cilia and for trafficking within primary cilia . IFT-A has historically been believed to mediate retrograde intraflagellar transport inside the cilia. However, the binding of the IFT-A complex to TULP3 imparts IFT-A with a novel function of directing TULP3's entry into the cilia . Deletion analysis of the TULP3 amino terminus narrowed this binding region to a conserved helix in the amino terminus of the IFT-A-binding TULP members [26, 28] (Figure 1b). Furthermore, small interfering RNA (siRNA) depletion of individual subunits of the IFT-A complex showed that three subunits (WDR19, IFT122 and IFT140) form a 'core' IFT-A sub-complex (important in maintaining the stability of the holo-IFT-A complex) and that this core is important for binding to TULP3  (Figure 2c). It is interesting that this IFT-A binding region overlaps with a nuclear localization sequence [6, 26, 29]. Nuclear localization sequences and ciliary localization motifs often share similarities , suggesting evolutionary parallels in mechanisms for localization to these different cellular domains.
Other regions in the amino terminus of tubby family proteins have been proposed to have distinct functional motifs. For example, Tulp1 and Tub have been identified as phagocytosis-stimulating molecules in retinal pigment epithelium (RPE) cells and macrophages, using a phage display strategy [30, 31]. These proteins act as extracellular ligands of members of the TAM receptor tyrosine kinase subfamily, including MerTK . The minimal phagocytosis determinant has been mapped to five K/R(X)1-2KKK motifs in the mouse Tulp1 amino terminus, and combined mutagenesis of all five motifs abrogates its effect on RPE phagocytosis and MerTK binding . However, most of these sites in the mouse Tulp1 are poorly conserved even with other mammalian Tulp1 homologs, and the physiological relevance of MerTK binding remains unclear.
TULP4 and the plant tubby-like proteins also have distinct domains in their amino termini. TULP4 has a WD40 repeat region at positions 78 to 218 and a suppressor of cytokine signaling (SOCS) domain at positions 82 to 208  (Figure 1b). All of the Arabidopsis AtTLPs except AtTLP8 contain highly conserved F-box domains in their amino terminus [20, 32]. The F-box or SOCS box domain containing proteins act as bridges between specific substrates and generic components of the SCF-type (Skp1-Cullin-F-box) or ECS-type (ElonginC-cullin-SOCS-box) E3 ubiquitin ligase complexes, respectively [33, 34]. The F-box domain in AtTLP9 interacts with the Arabidopsis Skp1-like 1 or ASK1 protein , whereas human TULP4 interacts with cullin 5 and elongins B and C, generic components of E3 ubiquitin ligases (SM and PKJ, unpublished). However, the specific substrates for these E3 ubiquitin ligases are unknown.
In addition to the canonical function in PIP2 binding, the tubby domain has been proposed to have other functions. The tubby domain of Tub has been suggested to function in double-stranded DNA binding, an interaction depending largely on the positively charged surface of this domain . Fusing the amino-terminal half of the Tub or Tulp1 protein to the DNA-binding domain of GAL4 activated transcription of a reporter gene downstream of the GAL4 DNA-binding site . Another study using a protein microarray strategy detected DNA-binding motifs for TULP1 . However, the role of these proteins in transcriptional regulation is not clear, because clear downstream Tub/Tulp1-regulated genes have not been identified, and acidic-domain-GAL4 fusions can activate transcription nonspecifically. The tubby domain of Tub and Tulp1 is thought to function in binding to phagocytic debris . Purified Tulp1 and Tub were observed to bind the surface of apoptotic cells, as assayed by flow cytometry. This binding was especially dependent on the carboxy-terminal 54 amino acids of Tub/Tulp1 and did not depend on the conserved PIP2 binding central residues. However, the identity of the anchoring molecules for Tulp1/Tub on phagocytic cells and the physiological relevance of these proteins as phagocytic ligands for maintaining retinal homeostasis are unclear.
Localization and function
Studies on the tissue distribution and subcellular localization of the diverse members of the tubby family help clarify their functions. Tub is expressed in the retina and the brain, including the hippocampus, and the paraventricular, ventromedial and arcuate nuclei of the hypothalamus [3, 9]. Tulp1 and Tulp2 are mainly expressed in the retina and the testis, respectively . However, Tulp3 is broadly expressed during mouse development and retains a widespread expression pattern in the adult, including in the central nervous system [10, 11]. The related invertebrate homologs are also expressed in the nervous system. C. elegans tub-1 is expressed in ciliated neurons [18, 19] and fly TULP is expressed in a subset of neuroblasts in early stage embryos and more broadly in the nervous system in late-stage embryos . The distant family member Tulp4 is broadly expressed, including in the mouse brain and testis . In humans, the full-length transcript is detected in the brain, skeletal muscle and kidney and a smaller transcript is strongly expressed in the heart and kidney . Fly TUSP is detected in bilateral groups of brain cells and in the antennal-maxillary sensory neurons in the embryos . Most of the plant TULPs are expressed ubiquitously except AtTLP5 and AtTLP8, which have a more restricted expression .
The tubby family proteins have been reported to localize to cytoplasmic, plasma membrane and nuclear fractions in transiently transfected cells and in stable cultured cell lines [5, 16, 26, 37]. TUB has at least two alternative splice forms, differing in their amino termini, encoding predicted proteins of 561 and 506 amino acids [26, 37]. Immunohistochemical analyses using an antibody capable of detecting both the isoforms show Tub to be localized notably in high concentrations in the nucleoli of brain neurons, with lower protein levels in the cytoplasm . In addition, in transfected cells, mutations in the conserved PIP2-binding residues of Tub result in its translocation to the nucleus , suggesting that membrane association anchors Tub to sequester it from transport to the nucleus. Tulp1 is expressed exclusively in the photoreceptors, localizing to the inner segment, connecting cilia, perikarya and synaptic terminals [38, 39]. Clonal stable lines of tubby family proteins in cultured cells suggest that TULP2 and TULP4 are exclusively cytoplasmic [7, 26]. Tulp3 is detected in both the cytoplasmic and nuclear fractions of mouse embryo extracts . In TULP3-expressing stable cell lines, inhibition of nuclear export using leptomycin-B or mutations in its conserved PIP2 binding residues results in its translocation to the nucleus . In the cytoplasm, Tulp3/TULP3 is localized to the primary ciliary base and also to punctate spots throughout the cilia, a localization observed in a wide range of cultured ciliated cells, including mouse embryonic fibroblasts [16, 26]. The localization of TULP3/Tulp3 to the cilia is strongly dependent on its binding to the core-IFT-A proteins, as siRNA-mediated depletion (WDR19, IFT122 and IFT140) or knockouts (Ift122) prevent its ciliary localization [26, 40] (Figure 2b). However, the holo-IFT-A complex also regulates retrograde intraflagellar transport of TULP3 inside the cilia, as depletion of other accessory components of the IFT-A complex (THM1 and WDR35, which are not important in maintaining core IFT-A complex architecture) results in its being accumulated at ciliary tips. Therefore, the IFT-A complex not only provides ciliary access to TULP3, but also regulates its retrograde transport inside the primary cilia .
Defects in the tubby-family proteins result in characteristic phenotypes and severe disease syndromes. The tubby mouse shows maturity-onset obesity, blindness and deafness. Obesity in tubby mice is slowly progressive, with weights beginning to diverge at about 12 to 16 weeks and subsequently reaching twice that of wild-type controls [1, 41]. Along with the weight gain, the tubby mice show increased insulin levels (insulin resistance) but normal glucose levels (normoglycemic) [1, 41]. Even before the onset of obesity, the earliest defects in metabolism in the tubby mice seem to be a paradoxical failure to use carbohydrates as an energy source and an increased reliance on fat metabolism and β-oxidation (used normally during starvation for energy needs) . Although tubby mice increase food intake as they age, their food intake surpasses that of wild-type controls only after they weigh significantly more, reflecting their need for higher energy to maintain the increased body mass . Hypothalamic mediators important in the central control of obesity, including neuropeptide Y (NPY), Agouti-related peptide (Agrp) and Orexin, are upregulated in the hypothalamus by 7 to 8 weeks, before the onset of obesity . After the onset of obesity, the tubby mice show altered levels of NPY and proopiomelanocortin (POMC) in the hypothalamus ; however, it is not clear whether these observed neurochemical changes are causative or arise as a consequence of the obesity syndrome. Aside from the central effects, Tub might also be a mediator of insulin signaling and energy metabolism in the adipose tissue [43, 44]. Tub is expressed in the adipose tissue, is upregulated in 3T3-L1 pre-adipocytes during adipocyte differentiation and is upregulated in insulin-resistant 3T3-L1 adipocytes . It is also tyrosine phosphorylated following insulin treatment in both neuronal PC12 and 3T3-L1 cells [43, 44]. In humans, TUB has been identified as a candidate gene influencing body weight  and polymorphisms of this gene are associated with body composition and eating behavior in middle-aged women . In addition to obesity, tubby mice also develop progressive neurosensory deficits, including retinal and cochlear degeneration . The cochlear degeneration is dependent on the presence of polymorphisms in the microtubule-associated protein gene Map1a in the C57BL/6J background; however, the biochemical mechanism of this genetic interaction is unclear . A null mutant of Tub is phenotypically indistinguishable from tubby mice with regard to weight gain and retinal degeneration .
TULP1 mutations in humans result in retinitis pigmentosa type 14, which is inherited in an autosomal recessive manner [12–14]. Null mutations of Tulp1 in mice result in early-onset (abnormal outer and inner segments by 2 weeks of age) and progressive photoreceptor degeneration [15, 39, 49]. The retinal degeneration in these knockout mice is earlier than in the tubby mice, and the visual deficits are finally associated with apoptosis of the retinal photoreceptors in both Tub and Tulp1 knockout mice. Tulp1 knockout retinal photoreceptors show mislocalization of rod and cone opsins in the inner segments even before the photoreceptor degeneration starts, suggesting that Tulp1 is important in intracellular vesicular trafficking . In addition, Tulp1 knockout mice show early defects in photoreceptor synapses and stunting of bipolar dendrites at stages before retinal degeneration, suggesting that Tulp1 might be critical for normal development of the photoreceptor synapse . Double knockouts of Tulp1 and tubby show more rapid retinal degeneration than either single knockout .
Tulp3 mutant mice show embryonic lethality on or before embryonic day 14.5 and have defects, including exencephaly, spina bifida, micropthalmia and polydactyly [10, 16, 17, 50]. On closer inspection, the lumbar neural tube shows increased Shh signaling apparent from the ventralization of the neuronal subtypes [16, 17]. Similar phenotypes are present in mutants of IFT-A complex subunits Ift122 and Thm1 [40, 51, 52].
Currently, there are no knockouts for either mouse Tulp2 or Tulp4. However, the C. elegans tub-2 was identified in an RNA interference (RNAi) screen for altered innate immune responsiveness, and siRNA-mediated depletion of Tulp4 decreased production of the cytokine interleukin-6 in murine macrophages in response to bacterial lipopolysaccharides . Of the plant tubby family members, mutants of AtTLP9 are abscisic-acid-insensitive, suggesting that AtTLP9 is important in the abscisic acid signaling pathway . Expression of the members of the rice tubby family is induced on infection with microorganisms that cause bacterial blight, suggesting a role in host-pathogen interactions .
The tubby-mouse syndrome belongs to a growing class of monogenic obesity syndromes that includes congenital leptin deficiency and leptin receptor deficiency . Recent studies suggest that monogenic obesity syndromes can also be caused by defects in neuronal cilia or defects in trafficking to this compartment. For example, disruption of intraflagellar transport in adult mice in the POMC-expressing hypothalamic axis results in hyperphagia-induced obesity . In addition, primary cilia in the central nervous system neurons are rich in G protein-coupled receptors (GPCRs) such as melanin concentrating hormone receptor (Mchr1 ) and downstream effectors such as adenylyl cyclase type 3 (ACIII ). Mchr1 is involved in the regulation of feeding and energy balance [59, 60], and ACIII-deficient mice become obese with age . Patients with complex developmental disorders such as Bardet-Biedl syndrome (BBS) also develop obesity, and a complex of proteins involved in BBS, known as the BBSome, has been shown to transport specific ciliary proteins [62–64]. The cause of obesity in the tubby mice has been attributed to defects in hypothalamic signaling, as Tub is highly expressed in the hypothalamus. However, the mechanism by which Tub regulates the neuroendocrine axis in regulating obesity is not clear and is one of the pressing questions that need to be addressed to understand the pathogenesis of obesity.
Other studies also suggest the role of these proteins in related vesicular trafficking processes. For example, the C. elegans TUB-1 interacts with a Rab GTPase-activating protein, RBG-3, in a yeast two-hybrid screen, and RNAi of rbg-3 reduces fat deposition in the tub-1 mutant , suggesting an evolutionarily conserved role of these proteins. Tulp1 is important in rhodopsin trafficking to the outer photoreceptor segment , and its association with dynamin-1, a protein implicated in endocytic vesicle trafficking, may be important in this process . Cellular signaling might in turn affect tubby domain containing proteins, and this adds another level of functional complexity in their regulation. This is exemplified by the regulated dislodgement of this domain from the plasma membrane on activation of Gαq-coupled GPCRs. Activation of these GPCRs result in changes in membrane PIP2 levels and subsequent translocation of transfected Tub to the nucleus  (Figure 3b). Thus, the tubby family proteins promote vesicular trafficking in a highly regulated manner, and future research should focus on the role of these processes in the tubby-mouse syndrome.
A recurring functional feature of this class of proteins is their involvement in diverse signaling processes. For example, Tulp3 is expressed early during mouse development and, notably, mutations in Tulp3 result in developmental defects in Shh-dependent dorso-ventral patterning of the neural tube [16, 17]. Similar phenotypes are observed in the IFT-A mutants [40, 51, 52]. IFT-A associates with Tulp3 and has both an early role in delivering Tulp3 to the cilia and another role in retrograde ciliary traffic of Tulp3, compromising Tulp3 function in either case. This explains why the Tulp3 and IFT-A complex act coordinately as negative regulators of the Shh signaling pathway. However, it is not clear how Tulp3-IFT-A regulates Shh signaling. The frizzled family GPCR Smoothened (Smo) is trafficked to the cilia in a Shh-dependent manner . However, Tulp3 does not regulate Smo trafficking to the cilia [16, 26], and genetic epistasis experiments suggest that, similar to the IFT-A subunit mutants, Tulp3 restricts activity of the transcription factor Gli2 in an intraflagellar transport-dependent manner downstream of Shh and Smo . Besides, Gli3 processing is not impaired [16, 17, 26]. As TULP3 regulates GPCR trafficking in a wide variety of ciliated cells, defects in the developmental patterning of the neural tube could be regulated by the trafficking of a GPCR other than Smo. In addition, the Tulp3-IFT-A interactome would shed new light on the mechanisms by which the negative regulation on the Shh pathway is achieved. Future research should be directed towards the discovery of the key players important in Tulp3-mediated developmental patterning.
Since the positional cloning of Tub in 1996, studies on Tub and related family members are starting to provide us with remarkable insights into the tubby-mouse syndrome and related diseases. These molecules have now been shown to have major roles in coordinating multiple signaling pathways, including ciliary GPCR trafficking and Shh signaling during development. The emerging paradigm of these proteins serving as bipartite bridges, through their phosphoinositide-binding tubby and unique amino-terminal functional domains, simplifies the inherent complexity of their diverse functional attributes. Better understanding of the mechanisms of action of this protein family promises novel therapeutic targets for treating obesity.
- Coleman DL, Eicher EM: Fat (fat) and tubby (tub): two autosomal recessive mutations causing obesity syndromes in the mouse. J Hered. 1990, 81: 424-427.PubMed
- Ohlemiller KK, Hughes RM, Mosinger-Ogilvie J, Speck JD, Grosof DH, Silverman MS: Cochlear and retinal degeneration in the tubby mouse. Neuroreport. 1995, 6: 845-849. 10.1097/00001756-199504190-00005.PubMedView Article
- Kleyn PW, Fan W, Kovats SG, Lee JJ, Pulido JC, Wu Y, Berkemeier LR, Misumi DJ, Holmgren L, Charlat O, Woolf EA, Tayber O, Brody T, Shu P, Hawkins F, Kennedy B, Baldini L, Ebeling C, Alperin GD, Deeds J, Lakey ND, Culpepper J, Chen H, Glücksmann-Kuis MA, Carlson GA, Duyk GM, Moore KJ: Identification and characterization of the mouse obesity gene tubby: a member of a novel gene family. Cell. 1996, 85: 281-290. 10.1016/S0092-8674(00)81104-6.PubMedView Article
- Noben-Trauth K, Naggert JK, North MA, Nishina PM: A candidate gene for the mouse mutation tubby. Nature. 1996, 380: 534-538. 10.1038/380534a0.PubMedView Article
- Boggon TJ, Shan WS, Santagata S, Myers SC, Shapiro L: Implication of tubby proteins as transcription factors by structure-based functional analysis. Science. 1999, 286: 2119-2125. 10.1126/science.286.5447.2119.PubMedView Article
- Santagata S, Boggon TJ, Baird CL, Gomez CA, Zhao J, Shan WS, Myszka DG, Shapiro L: G-protein signaling through tubby proteins. Science. 2001, 292: 2041-2050. 10.1126/science.1061233.PubMedView Article
- Li QZ, Wang CY, Shi JD, Ruan QG, Eckenrode S, Davoodi-Semiromi A, Kukar T, Gu Y, Lian W, Wu D, She JX: Molecular cloning and characterization of the mouse and human TUSP gene, a novel member of the tubby superfamily. Gene. 2001, 273: 275-284. 10.1016/S0378-1119(01)00582-0.PubMedView Article
- North MA, Naggert JK, Yan Y, Noben-Trauth K, Nishina PM: Molecular characterization of TUB, TULP1, and TULP2, members of the novel tubby gene family and their possible relation to ocular diseases. Proc Natl Acad Sci USA. 1997, 94: 3128-3133. 10.1073/pnas.94.7.3128.PubMedPubMed CentralView Article
- Ikeda A, Naggert JK, Nishina PM: Genetic modification of retinal degeneration in tubby mice. Exp Eye Res. 2002, 74: 455-461. 10.1006/exer.2001.1139.PubMedView Article
- Ikeda A, Ikeda S, Gridley T, Nishina PM, Naggert JK: Neural tube defects and neuroepithelial cell death in Tulp3 knockout mice. Hum Mol Genet. 2001, 10: 1325-1334. 10.1093/hmg/10.12.1325.PubMedView Article
- Nishina PM, North MA, Ikeda A, Yan Y, Naggert JK: Molecular characterization of a novel tubby gene family member, TULP3, in mouse and humans. Genomics. 1998, 54: 215-220. 10.1006/geno.1998.5567.PubMedView Article
- Banerjee P, Kleyn PW, Knowles JA, Lewis CA, Ross BM, Parano E, Kovats SG, Lee JJ, Penchaszadeh GK, Ott J, Jacobson SG, Gilliam TC: TULP1 mutation in two extended Dominican kindreds with autosomal recessive retinitis pigmentosa. Nat Genet. 1998, 18: 177-179. 10.1038/ng0298-177.PubMedView Article
- Gu S, Lennon A, Li Y, Lorenz B, Fossarello M, North M, Gal A, Wright A: Tubby-like protein-1 mutations in autosomal recessive retinitis pigmentosa. Lancet. 1998, 351: 1103-1104. 10.1016/S0140-6736(05)79384-3.PubMedView Article
- Hagstrom SA, North MA, Nishina PL, Berson EL, Dryja TP: Recessive mutations in the gene encoding the tubby-like protein TULP1 in patients with retinitis pigmentosa. Nat Genet. 1998, 18: 174-176. 10.1038/ng0298-174.PubMedView Article
- Ikeda S, Shiva N, Ikeda A, Smith RS, Nusinowitz S, Yan G, Lin TR, Chu S, Heckenlively JR, North MA, Naggert JK, Nishina PM, Duyao MP: Retinal degeneration but not obesity is observed in null mutants of the tubby-like protein 1 gene. Hum Mol Genet. 2000, 9: 155-163. 10.1093/hmg/9.2.155.PubMedView Article
- Norman RX, Ko HW, Huang V, Eun CM, Abler LL, Zhang Z, Sun X, Eggenschwiler JT: Tubby-like protein 3 (TULP3) regulates patterning in the mouse embryo through inhibition of Hedgehog signaling. Hum Mol Genet. 2009, 18: 1740-1754. 10.1093/hmg/ddp113.PubMedPubMed CentralView Article
- Patterson VL, Damrau C, Paudyal A, Reeve B, Grimes DT, Stewart ME, Williams DJ, Siggers P, Greenfield A, Murdoch JN: Mouse hitchhiker mutants have spina bifida, dorso-ventral patterning defects and polydactyly: identification of Tulp3 as a novel negative regulator of the Sonic hedgehog pathway. Hum Mol Genet. 2009, 18: 1719-1739. 10.1093/hmg/ddp075.PubMedPubMed CentralView Article
- Mak HY, Nelson LS, Basson M, Johnson CD, Ruvkun G: Polygenic control of Caenorhabditis elegans fat storage. Nat Genet. 2006, 38: 363-368. 10.1038/ng1739.PubMedView Article
- Mukhopadhyay A, Deplancke B, Walhout AJ, Tissenbaum HA: C. elegans tubby regulates life span and fat storage by two independent mechanisms. Cell Metab. 2005, 2: 35-42. 10.1016/j.cmet.2005.06.004.PubMedView Article
- Lai CP, Lee CL, Chen PH, Wu SH, Yang CC, Shaw JF: Molecular analyses of the Arabidopsis TUBBY-like protein gene family. Plant Physiol. 2004, 134: 1586-1597. 10.1104/pp.103.037820.PubMedPubMed CentralView Article
- Yang Z, Zhou Y, Wang X, Gu S, Yu J, Liang G, Yan C, Xu C: Genomewide comparative phylogenetic and molecular evolutionary analysis of tubby-like protein family in Arabidopsis, rice, and poplar. Genomics. 2008, 92: 246-253. 10.1016/j.ygeno.2008.06.001.PubMedView Article
- Stolc V, Samanta MP, Tongprasit W, Marshall WF: Genome-wide transcriptional analysis of flagellar regeneration in Chlamydomonas reinhardtii identifies orthologs of ciliary disease genes. Proc Natl Acad Sci USA. 2005, 102: 3703-3707. 10.1073/pnas.0408358102.PubMedPubMed CentralView Article
- Bateman A, Finn RD, Sims PJ, Wiedmer T, Biegert A, Soding J: Phospholipid scramblases and Tubby-like proteins belong to a new superfamily of membrane tethered transcription factors. Bioinformatics. 2009, 25: 159-162. 10.1093/bioinformatics/btn595.PubMedPubMed CentralView Article
- Nelson CP, Nahorski SR, Challiss RA: Temporal profiling of changes in phosphatidylinositol 4,5-bisphosphate, inositol 1,4,5-trisphosphate and diacylglycerol allows comprehensive analysis of phospholipase C-initiated signalling in single neurons. J Neurochem. 2008, 107: 602-615. 10.1111/j.1471-4159.2008.05587.x.PubMedPubMed CentralView Article
- Quinn KV, Behe P, Tinker A: Monitoring changes in membrane phosphatidylinositol 4,5-bisphosphate in living cells using a domain from the transcription factor tubby. J Physiol. 2008, 586: 2855-2871. 10.1113/jphysiol.2008.153791.PubMedPubMed CentralView Article
- Mukhopadhyay S, Wen X, Chih B, Nelson CD, Lane WS, Scales SJ, Jackson PK: TULP3 bridges the IFT-A complex and membrane phosphoinositides to promote trafficking of G protein-coupled receptors into primary cilia. Genes Dev. 2010, 24: 2180-2193. 10.1101/gad.1966210.PubMedPubMed CentralView Article
- Rosenbaum JL, Witman GB: Intraflagellar transport. Nat Rev Mol Cell Biol. 2002, 3: 813-825. 10.1038/nrm952.PubMedView Article
- Rost B: PHD: predicting one-dimensional protein structure by profile-based neural networks. Methods Enzymol. 1996, 266: 525-539.PubMedView Article
- Dishinger JF, Kee HL, Jenkins PM, Fan S, Hurd TW, Hammond JW, Truong YN, Margolis B, Martens JR, Verhey KJ: Ciliary entry of the kinesin-2 motor KIF17 is regulated by importin-beta2 and RanGTP. Nat Cell Biol. 2010, 12: 703-710. 10.1038/ncb2073.PubMedPubMed CentralView Article
- Caberoy NB, Maiguel D, Kim Y, Li W: Identification of tubby and tubby-like protein 1 as eat-me signals by phage display. Exp Cell Res. 2010, 316: 245-257. 10.1016/j.yexcr.2009.10.008.PubMedPubMed CentralView Article
- Caberoy NB, Zhou Y, Li W: Tubby and tubby-like protein 1 are new MerTK ligands for phagocytosis. EMBO J. 2010, 29: 3898-3910. 10.1038/emboj.2010.265.PubMedPubMed CentralView Article
- Liu Q: Identification of rice TUBBY-like genes and their evolution. FEBS J. 2008, 275: 163-171.PubMedView Article
- Kile BT, Schulman BA, Alexander WS, Nicola NA, Martin HM, Hilton DJ: The SOCS box: a tale of destruction and degradation. Trends Biochem Sci. 2002, 27: 235-241. 10.1016/S0968-0004(02)02085-6.PubMedView Article
- Kipreos ET, Pagano M: The F-box protein family. Genome Biol. 2000, 1: reviews3002-PubMedPubMed CentralView Article
- Hu S, Xie Z, Onishi A, Yu X, Jiang L, Lin J, Rho HS, Woodard C, Wang H, Jeong JS, Long S, He X, Wade H, Blackshaw S, Qian J, Zhu H: Profiling the human protein-DNA interactome reveals ERK2 as a transcriptional repressor of interferon signaling. Cell. 2009, 139: 610-622. 10.1016/j.cell.2009.08.037.PubMedPubMed CentralView Article
- Ronshaugen M, McGinnis N, Inglis D, Chou D, Zhao J, McGinnis W: Structure and expression patterns of Drosophila TULP and TUSP, members of the tubby-like gene family. Mech Dev. 2002, 117: 209-215. 10.1016/S0925-4773(02)00211-3.PubMedView Article
- He W, Ikeda S, Bronson RT, Yan G, Nishina PM, North MA, Naggert JK: GFP-tagged expression and immunohistochemical studies to determine the subcellular localization of the tubby gene family members. Brain Res Mol Brain Res. 2000, 81: 109-117.PubMedView Article
- Grossman GH, Pauer GJ, Narendra U, Peachey NS, Hagstrom SA: Early synaptic defects in tulp1-/- mice. Invest Ophthalmol Vis Sci. 2009, 50: 3074-3083. 10.1167/iovs.08-3190.PubMedPubMed CentralView Article
- Hagstrom SA, Adamian M, Scimeca M, Pawlyk BS, Yue G, Li T: A role for the Tubby-like protein 1 in rhodopsin transport. Invest Ophthalmol Vis Sci. 2001, 42: 1955-1962.PubMed
- Qin J, Lin Y, Norman RX, Ko HW, Eggenschwiler JT: Intraflagellar transport protein 122 antagonizes Sonic Hedgehog signaling and controls ciliary localization of pathway components. Proc Natl Acad Sci USA. 2011, 108: 1456-1461. 10.1073/pnas.1011410108.PubMedPubMed CentralView Article
- Wang Y, Seburn K, Bechtel L, Lee BY, Szatkiewicz JP, Nishina PM, Naggert JK: Defective carbohydrate metabolism in mice homozygous for the tubby mutation. Physiol Genomics. 2006, 27: 131-140. 10.1152/physiolgenomics.00239.2005.PubMedView Article
- Guan XM, Yu H, Van der Ploeg LH: Evidence of altered hypothalamic pro-opiomelanocortin/neuropeptide Y mRNA expression in tubby mice. Brain Res Mol Brain Res. 1998, 59: 273-279.PubMedView Article
- Kapeller R, Moriarty A, Strauss A, Stubdal H, Theriault K, Siebert E, Chickering T, Morgenstern JP, Tartaglia LA, Lillie J: Tyrosine phosphorylation of tub and its association with Src homology 2 domain-containing proteins implicate tub in intracellular signaling by insulin. J Biol Chem. 1999, 274: 24980-24986. 10.1074/jbc.274.35.24980.PubMedView Article
- Stretton C, Litherland GJ, Moynihan A, Hajduch E, Hundal HS: Expression and modulation of TUB by insulin and thyroid hormone in primary rat and murine 3T3-L1 adipocytes. Biochem Biophys Res Commun. 2009, 390: 1328-1333. 10.1016/j.bbrc.2009.10.147.PubMedView Article
- Shiri-Sverdlov R, Custers A, van Vliet-Ostaptchouk JV, van Gorp PJ, Lindsey PJ, van Tilburg JH, Zhernakova S, Feskens EJ, van der AD, Dollé ME, van Haeften TW, Koeleman BP, Hofker MH, Wijmenga C: Identification of TUB as a novel candidate gene influencing body weight in humans. Diabetes. 2006, 55: 385-389. 10.2337/diabetes.55.02.06.db05-0997.PubMedView Article
- van Vliet-Ostaptchouk JV, Onland-Moret NC, Shiri-Sverdlov R, van Gorp PJ, Custers A, Peeters PH, Wijmenga C, Hofker MH, van der Schouw YT: Polymorphisms of the TUB gene are associated with body composition and eating behavior in middle-aged women. PLoS One. 2008, 3: e1405-10.1371/journal.pone.0001405.PubMedPubMed CentralView Article
- Ikeda A, Zheng QY, Zuberi AR, Johnson KR, Naggert JK, Nishina PM: Microtubule-associated protein 1A is a modifier of tubby hearing (moth1). Nat Genet. 2002, 30: 401-405. 10.1038/ng838.PubMedPubMed CentralView Article
- Stubdal H, Lynch CA, Moriarty A, Fang Q, Chickering T, Deeds JD, Fairchild-Huntress V, Charlat O, Dunmore JH, Kleyn P, Huszar D, Kapeller R: Targeted deletion of the tub mouse obesity gene reveals that tubby is a loss-of-function mutation. Mol Cell Biol. 2000, 20: 878-882. 10.1128/MCB.20.3.878-882.2000.PubMedPubMed CentralView Article
- Hagstrom SA, Duyao M, North MA, Li T: Retinal degeneration in tulp1-/- mice: vesicular accumulation in the interphotoreceptor matrix. Invest Ophthalmol Vis Sci. 1999, 40: 2795-2802.PubMed
- Cameron DA, Pennimpede T, Petkovich M: Tulp3 is a critical repressor of mouse hedgehog signaling. Dev Dyn. 2009, 238: 1140-1149. 10.1002/dvdy.21926.PubMedView Article
- Tran PV, Haycraft CJ, Besschetnova TY, Turbe-Doan A, Stottmann RW, Herron BJ, Chesebro AL, Qiu H, Scherz PJ, Shah JV, Yoder BK, Beier DR: THM1 negatively modulates mouse sonic hedgehog signal transduction and affects retrograde intraflagellar transport in cilia. Nat Genet. 2008, 40: 403-410. 10.1038/ng.105.PubMedView Article
- Ocbina PJ, Eggenschwiler JT, Moskowitz I, Anderson KV: Complex interactions between genes controlling trafficking in primary cilia. Nat Genet. 2011, 43: 547-553. 10.1038/ng.832.PubMedPubMed CentralView Article
- Alper S, Laws R, Lackford B, Boyd WA, Dunlap P, Freedman JH, Schwartz DA: Identification of innate immunity genes and pathways using a comparative genomics approach. Proc Natl Acad Sci USA. 2008, 105: 7016-7021. 10.1073/pnas.0802405105.PubMedPubMed CentralView Article
- Kou Y, Qiu D, Wang L, Li X, Wang S: Molecular analyses of the rice tubby-like protein gene family and their response to bacterial infection. Plant Cell Rep. 2009, 28: 113-121. 10.1007/s00299-008-0620-z.PubMedView Article
- Farooqi IS, O'Rahilly S: Monogenic human obesity syndromes. Recent Prog Horm Res. 2004, 59: 409-424. 10.1210/rp.59.1.409.PubMedView Article
- Davenport JR, Watts AJ, Roper VC, Croyle MJ, van Groen T, Wyss JM, Nagy TR, Kesterson RA, Yoder BK: Disruption of intraflagellar transport in adult mice leads to obesity and slow-onset cystic kidney disease. Curr Biol. 2007, 17: 1586-1594. 10.1016/j.cub.2007.08.034.PubMedPubMed CentralView Article
- Berbari NF, Lewis JS, Bishop GA, Askwith CC, Mykytyn K: Bardet-Biedl syndrome proteins are required for the localization of G protein-coupled receptors to primary cilia. Proc Natl Acad Sci USA. 2008, 105: 4242-4246. 10.1073/pnas.0711027105.PubMedPubMed CentralView Article
- Bishop GA, Berbari NF, Lewis J, Mykytyn K: Type III adenylyl cyclase localizes to primary cilia throughout the adult mouse brain. J Comp Neurol. 2007, 505: 562-571. 10.1002/cne.21510.PubMedView Article
- Chen Y, Hu C, Hsu CK, Zhang Q, Bi C, Asnicar M, Hsiung HM, Fox N, Slieker LJ, Yang DD, Heiman ML, Shi Y: Targeted disruption of the melanin-concentrating hormone receptor-1 results in hyperphagia and resistance to diet-induced obesity. Endocrinology. 2002, 143: 2469-2477. 10.1210/en.143.7.2469.PubMedView Article
- Shimada M, Tritos NA, Lowell BB, Flier JS, Maratos-Flier E: Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature. 1998, 396: 670-674. 10.1038/25341.PubMedView Article
- Wang Z, Li V, Chan GC, Phan T, Nudelman AS, Xia Z, Storm DR: Adult type 3 adenylyl cyclase-deficient mice are obese. PLoS One. 2009, 4: e6979-10.1371/journal.pone.0006979.PubMedPubMed CentralView Article
- Nachury MV, Loktev AV, Zhang Q, Westlake CJ, Peranen J, Merdes A, Slusarski DC, Scheller RH, Bazan JF, Sheffield VC, Jackson PK: A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell. 2007, 129: 1201-1213. 10.1016/j.cell.2007.03.053.PubMedView Article
- Jin H, White SR, Shida T, Schulz S, Aguiar M, Gygi SP, Bazan JF, Nachury MV: The conserved Bardet-Biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia. Cell. 2010, 141: 1208-1219. 10.1016/j.cell.2010.05.015.PubMedPubMed CentralView Article
- Lechtreck KF, Johnson EC, Sakai T, Cochran D, Ballif BA, Rush J, Pazour GJ, Ikebe M, Witman GB: The Chlamydomonas reinhardtii BBSome is an IFT cargo required for export of specific signaling proteins from flagella. J Cell Biol. 2009, 187: 1117-1132. 10.1083/jcb.200909183.PubMedPubMed CentralView Article
- Xi Q, Pauer GJ, Ball SL, Rayborn M, Hollyfield JG, Peachey NS, Crabb JW, Hagstrom SA: Interaction between the photoreceptor-specific tubby-like protein 1 and the neuronal-specific GTPase dynamin-1. Invest Ophthalmol Vis Sci. 2007, 48: 2837-2844. 10.1167/iovs.06-0059.PubMedPubMed CentralView Article
- Corbit KC, Aanstad P, Singla V, Norman AR, Stainier DY, Reiter JF: Vertebrate Smoothened functions at the primary cilium. Nature. 2005, 437: 1018-1021. 10.1038/nature04117.PubMedView Article
- Kumar S, Tamura K, Nei M: MEGA: Molecular Evolutionary Genetics Analysis software for microcomputers. Comput Appl Biosci. 1994, 10: 189-191.PubMed