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Transcription Transcription factor Tubby signaling pathways


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Transcription Transcription factor Tubby signaling pathways

Transcription factor Tubby signaling pathways

The Tubby homolog ( TUB ) is a member of the family of four homologous proteinsthat includes TUB and TULPs 1-3. These proteins are found in humans and othermulticellular organisms.

They form a novel small gene family that plays an important role in the maintenanceand function of neuronal cells during the development and post-differentiation. TheTUB gene is highly expressed in the paraventricular nucleus of the hypothalamusand several other brain regions [1], [2].

TUB functions as a transcription regulator, but details of the molecularmechanism of its activity remain unclear. It was shown that members of the tubby familyserve as downstream effectors of G-protein coupled receptors,   that signalthrough the G-protein alpha-q/11 subclass of G-alpha proteins, such as5-hydroxytryptamine (serotonin) receptor 2C ( HTR2C (HTR1C) ) [1].

Activation of the HTR2C (HTR1C) results in the activation of G-proteinalpha-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 involvedin the activation of TUB.

TUB is localized in the plasma membrane via binding to the phosphatidylinositol4,5-bisphosphate ( PtdIns(4,5)P2 ). Its carboxyl terminal "tubby' domain though islikely to be associated with the membrane-bound G-protein alpha-q/11. ActivePLC-beta cleaves PtdIns(4,5)P2 leading to release of the TUB fromthe plasma membrane and its translocation to the nucleus [1].

TUB is also believed to participate in the Insulin receptor signalingpathway. The Insulin receptor is a member of a large family of transmembraneprotein-tyrosine kinases, is widely distributed in the central nervous system. Thebinding of Insulin to its cell surface receptor initiates phosphorylation ofdownstream targets, including the Insulin receptor substrate 1 (IRS-1), a member of agrowing family of adaptor proteins that link upstream kinases to downstream signalingpathways. Like the IRS-1, TUB, can be phosphorylated by the Insulinreceptor protein-tyrosine kinase. It can also be phosphorylated by c-abl oncogene 1,receptor tyrosine kinase ( c-Abl ) and Janus kinase 2 ( JAK2 ). Similarlyto the IRS-1, TUB can also bind to various SH2-containing signaling molecules,such as Phospholipase C gamma ( PLC-gamma ) . This implicates adaptorfunction of TUB and the possible role of TUB in linking the Insulinreceptor to downstream signaling protein cascades [3].