G Protein Signaling Mediated by Tubby

Tubby is the founding member of a multigene protein family that plays an important role in maintenance and function of neuronal cells during development and post-differentiation. Currently, four tubby gene family members (TUB, TULP1, TULP2 and TULP3) have been identified, which are conserved among different species of mammals. Tubby-like proteins are also found in other multicellular organisms including plants. These proteins feature a characteristic 'Tubby' domain of approximately 260 amino acids at the C-terminus that forms a unique helix-filled barrel structure. This C-terminal domain binds avidly to double-stranded DNA. Most tubby proteins include NH2-terminal regions that in general are not closely related to one another. These NH2-terminal regions, however, are often similar in cross-species orthologs. They comprise about 180 to 280 amino acids in Tubby and TULPs 1 through 3.Tubby has been implicated as a transcription regulator. It transduces its signal via GPCRs and G-proteins. Tubby localizes to the plasma membrane by binding PIP2 through its carboxyl terminal Tubby domain. Receptor-mediated activation of Gαq releases Tubby from the plasma membrane through the action of PLC-β, triggering translocation of Tubby to the nucleus. In the nucleus, Tubby binds to DNA and regulates transcription. The localization of TULP3 is similarly regulated. Thus Tubby proteins are found to provide a direct link between G-protein signaling and the regulation of gene expression.Some GPCRs such as 5-HT2c, bombesin, MCH, MC4, and D1 receptors may signal in part through Tubby in addition to calcium mediated and protein kinase signaling pathways. Tubby also functions in insulin receptor signaling. It may be directly phosphorylated by IRK, as well as by Abl and JAK2 kinases. The phosphorylated form of Tubby appears to bind to the SH2 domains of Abl, LCK and PLC-γ. Therefore, Tubby functions as an adapter protein linking the insulin receptor to SH2-containing proteins. Tubby has also been implicated in mediating leptin receptor signaling. In mammals, mutation of Tubby or other TULPs can result in one or more of three disease phenotypes: obesity (from which the name 'Tubby' is derived), retinal degeneration, and hearing loss. These disease phenotypes indicate a vital role for Tubby proteins. However, no biochemical function has yet been ascribed to any member of this protein family.