G-Protein Signaling through Tubby Protein
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G-Protein Signaling through Tubby Protein

The Tubby protein 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 (Ref.1). Besides, 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 (Ref.2).

Tubby has been implicated as a transcription regulator. Tubby functions in signal transduction from heterotrimeric GTP-binding protein through GPCR (G-Protein Coupled Receptors,). Tubby is transported from the plasma membrane to the nucleus through G-AlphaQ activation. Tubby localizes to the plasma membrane by binding PIP2 (Phosphatidylinositol-4, 5-Bisphosphate), a phospholipid that is highly enriched in the plasma membrane, through its carboxyl terminal “Tubby domain". Receptor-mediated activation of G-AlphaQ releases Tubby from the plasma membrane through the action of PLC-Beta (Phospholipase-C-Beta), triggering translocation of Tubby to the cell nucleus and with the release of second messenger IP3 (Inositol 1,4,5-Trisphosphate) (Ref.3). In the nucleus, it binds to DNA and regulates transcription. The localization of TULP3 (Tubby-Like Protein-3) is similarly regulated. Thus Tubby proteins are found to provide a direct link between G-protein signaling and the regulation of gene expression. The G-AlphaQ family member G-Alpha11 functions to induce Tubby translocation in a manner identical to that of G-AlphaQ. Active G-Alpha11 induced total nuclear translocation of Tubby. Some GPCRs such as 5-HT2c, bombesin, MCH (Melanin Concentrating Hormone), MC4 (Melanocortin-4), and D1 (Dopamine-1) receptors may signal in part through Tubby in addition to calcium-mediated pathways and protein kinase signaling pathways (Ref.4).

TUB can also serve as a substrate for the Insulin Receptor protein tyrosine kinase. It may function as a link to a diverse array of downstream signaling pathways. Tub may be directly phosphorylated by the IRK (Insulin Receptor Kinase), as well as by Abl (v-Abl Abelson Murine Leukemia Viral Oncogene Homolog-1) and JAK2 (Janus Kinase-2) kinases. The phosphorylated form of Tub appears to bind to the SH2 (Src homology-2) domains of Abl, Lck (Lymphocyte-Specific Protein-Tyrosine Kinase) and PLC-Gamma (Phospholipase-C-Gamma). Therefore, Tub might function as an adapter protein, linking the Insulin Receptor to SH2-containing proteins. Tub, like IRS1, may also serve as a substrate for JAK2, which has been implicated in mediating Leptin receptor signaling. In mammals, genetic 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 (Ref.5).