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Tubby proteins: the plot thickens

Nature Reviews Molecular Cell Biology volume 5, pages 55–64 (2004)Cite this article

Key Points

  • TUB is the founding member of the tubby-like proteins, or TULPs. TULPs are found in multicellular organisms from both the plant and animal kingdoms, which indicates an ancient and fundamental function.

  • The TULP family of proteins has neuronal expression patterns in the retina and cochlea, and throughout the brain. TULPs have been shown to have a role in obesity, sensoneuronal degeneration, and development; and ablation of certain TULPs has been shown to be responsible for obesity and retinitis pigmentosa.

  • The TULPs are characterized by a highly conserved domain of about 260 amino acids — the 'tubby' domain — which is located at the carboxyl terminus of all TULP-family proteins.

  • The tubby domain has been shown to bind double-stranded DNA, and certain amino-terminal splice forms of the mouse TUB protein have been shown to activate transcription. Furthermore, the TUB protein has been shown to localize to both the cell membrane and the nucleus. These data have led to the hypothesis that TULPs might function in transcription.

  • Compelling evidence shows that TULPs respond to signals from activated heterotrimeric G-proteins of the Gαq/11 family, which function through a phospholipase-Cβ-dependent pathway to mediate translocation of TUB from the plasma membrane to the nucleus.

  • Other evidence also implicates TUB in neuronal synapse function, and rhodopsin transport. This variety of seemingly disparate results, when reconciled, might place TULPs at a central point in the integration of a number of cellular signals.

Abstract

The tubby mouse, which shows late-onset obesity and neurosensory deficits, arises from a mutation in the Tub gene. Tub shares homology with the genes for tubby-like proteins Tulp1, Tulp2 and Tulp3. Ablation of Tub, Tulp1 or Tulp3 causes disease phenotypes that are indicative of their importance in nervous-system function and development. Despite this importance, the biochemical functions of tubby-like proteins are only now beginning to be understood. At present, data indicate that tubby-like proteins might function as heterotrimeric-G-protein-responsive intracellular signalling factors, although an array of data also implicates them in other processes.

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Figure 1: A diagram of the TUB protein.
Figure 2: The present picture of TUB biochemical activity.
Figure 3: Tulp loss and retinal degeneration.
Figure 4: Tulps in neural-tube closure.
Figure 5: Ribbon diagram of the carboxy-terminal domain from Tub.
Figure 6: Tub–phosphoinositol binding.

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Acknowledgements

We thank S. Patel and K. Simpson for critical reading of the manuscript. This work was supported by a grant from the American Diabetes Association and the National Institutes of Health.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biophysics, Columbia University, 701 West 168th Street, Room 712, New York, 10032, New York, USA

    Kilpatrick Carroll & Lawrence Shapiro

  2. Edward S. Harkness Eye Institute, Columbia University, New York, 10032, New York, USA

    Carlos Gomez & Lawrence Shapiro

  3. Naomi Berrie Diabetes Center, Columbia University, New York, 10032, New York, USA

    Lawrence Shapiro

Authors
  1. Kilpatrick Carroll
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  2. Carlos Gomez
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Correspondence to Lawrence Shapiro.

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Related links

Related links

DATABASES

LocusLink

Tulp2

TULPs

OMIM

retinitis pigmentosa type 14

Interpro

tubby domain

GPCRs

Swiss-Prot

CART

corticotropin-releasing hormone

galanin

leptin

melanin-concentrating hormone

microtubule-associated protein 1A

neuropeptide Y

pro-opiomelanocortin

Tub

TULP1

TULP3

Glossary

COCHLEAR ORGAN OF CORTI

A complex epithelial structure in the cochlea that rests on the internal surface of the basilar membrane, and in mammals is the main part of the ear that directly perceives sound.

INSULIN RESISTANCE

An animal is said to be insulin resistant if abnormally high insulin levels are required to elicit typical physiological effects, such as lowering glucose levels in the bloodstream.

HETEROTRIMERIC G-PROTEIN

A protein complex of three proteins (Gα, Gβ and Gγ). Whereas Gβ and Gγ form a tight complex, Gα is part of the complex in its inactive, GDP-bound, form but dissociates in its active, GTP-bound, form. Both Gα and Gβγ can transmit downstream signals after activation.

RETINITIS PIGMENTOSA

Any of several hereditary, progressive, degenerative diseases of the eye that are marked by night blindness in the early stages, atrophy and pigment changes in the retina, constriction of the visual field, and eventual blindness.

ELECTRORETINOGRAPHY

A method for measuring changes in the electrical potential of the retina when it is stimulated by light.

ROD PHOTORECEPTOR CELLS

Columnar cells (about 40 μm long and 1 μm wide) that have three distinct regions: a region adjacent to (and synapsed with) the neural layer of the retina contains the nucleus and other cytoplasmic organelles; below this is the inner segment, which is rich in mitochondria; this, in turn, is connected through a thin neck (in which a ciliary body is located) to the outer segment.

CONE PHOTORECEPTOR CELLS

Cone-shaped cells of the vertebrate retina, which, in mammals, contain the photopigment iodopsin. Human cone cells are thought to occur in three types, which contain iodopsins of different spectral sensitivities. Therefore, they are thought to be responsible for colour vision.

CONE-ROD DYSTROPHY

An inherited, progressive disease that causes deterioration of the cone and rod photoreceptor cells and often results in blindness. It can be found as an autosomal-dominant trait, but it is usually acquired in an autosomal-recessive way. It is similar to retinitis pigmentosa in this way, but does not cause loss of night vision, although rod and cone degeneration is equivalent.

TRANSVERSION

A point mutation in which a purine base is substituted for a pyrimidine base and vice versa.

ARCUATE NUCLEUS

A nucleus located in the middle hypothalamus in the most ventral part of the third ventricle near the entrance of the infundibular recess.

PHALANGEAL CELLS

Cells of the organ of Corti (in the inner ear).

GANGLION CELL

A type of interneuron that conveys information from the retinal bipolar, horizontal and amacrine cells to the brain.

SUPPORT CELLS

Cells that completely surround the inner hair cells. The physiological function of the several supporting cell types of the organ of Corti, such as Hensen's cells, Deiters' cells, border cells, and inner phalangeal cells, is obscure.

EXENCEPHALY

A condition in which the skull is defective, with the brain extruding.

ACID-GLOBULE ACTIVATION DOMAIN

A protein domain that is rich in acidic amino acids and is known to activate transcription. It is commonly found in transcription factors.

HYPERINSULINAEMIA

An endocrine disorder that is characterized by a failure of the blood-sugar control system to work properly, and occurs when insulin progressively loses its effectiveness in removing the blood glucose from the bloodstream.

PC12 CELLS

A clonal line of rat adrenal pheochromocytoma cells that respond to nerve growth factor and can synthesize, store and secrete catecholamines in a similar way to sympathetic neurons. PC12 cells contain small, clear, synaptic-like vesicles and larger, dense-core granules.

SH2 DOMAIN

(Src-homology-2 domain). A protein motif that recognizes and binds tyrosine-phosphorylated sequences, and thereby has a key role in relaying cascades of signal transduction.

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Carroll, K., Gomez, C. & Shapiro, L. Tubby proteins: the plot thickens. Nat Rev Mol Cell Biol 5, 55–64 (2004). https://doi.org/10.1038/nrm1278

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