PLC-gamma, PLC-beta, DAG, IP3, Serotonin extracellular region, Insulin, G-protein alpha-q/11, 22.214.171.124, c-Abl, G-protein alpha-11, PtdIns(4,5)P2, PKC, HTR2C (HTR1C), Insulin receptor, JAK2, TUB, G-protein alpha-q
Transcription factor Tubby signaling pathways
The Tubby homolog ( TUB ) is a member of the family of four homologous proteins that includes TUB and TULPs 1-3. These proteins are found in humans and other multicellular organisms.
They form a novel small gene family that plays an important role in the maintenance and function of neuronal cells during the development and post-differentiation. The TUB gene is highly expressed in the paraventricular nucleus of the hypothalamus and several other brain regions , .
TUB functions as a transcription regulator, but details of the molecular mechanism of its activity remain unclear. It was shown that members of the tubby family serve as downstream effectors of G-protein coupled receptors, that signal through the G-protein alpha-q/11 subclass of G-alpha proteins, such as 5-hydroxytryptamine (serotonin) receptor 2C ( HTR2C (HTR1C) ) .
Activation of the HTR2C (HTR1C) results in the activation of G-protein alpha-q/11. G-protein alpha-q/11 in turn interacts with Phospholipase C beta ( PLC-beta) and activates it. G-protein alpha-q/11 was shown to be involved in the activation of TUB.
TUB is localized in the plasma membrane via binding to the phosphatidylinositol 4,5-bisphosphate ( PtdIns(4,5)P2 ). Its carboxyl terminal "tubby' domain though is likely to be associated with the membrane-bound G-protein alpha-q/11. Active PLC-beta cleaves PtdIns(4,5)P2 leading to release of the TUB from the plasma membrane and its translocation to the nucleus .
TUB is also believed to participate in the Insulin receptor signaling pathway. The Insulin receptor is a member of a large family of transmembrane protein-tyrosine kinases, is widely distributed in the central nervous system. The binding of Insulin to its cell surface receptor initiates phosphorylation of downstream targets, including the Insulin receptor substrate 1 (IRS-1), a member of a growing family of adaptor proteins that link upstream kinases to downstream signaling pathways. Like the IRS-1, TUB, can be phosphorylated by the Insulin receptor protein-tyrosine kinase. It can also be phosphorylated by c-abl oncogene 1, receptor tyrosine kinase ( c-Abl ) and Janus kinase 2 ( JAK2 ). Similarly to the IRS-1, TUB can also bind to various SH2-containing signaling molecules, such as Phospholipase C gamma ( PLC-gamma ) . This implicates adaptor function of TUB and the possible role of TUB in linking the Insulin receptor to downstream signaling protein cascades .