Pathway Map Details

Transcription_Transcription factor Tubby signaling pathways

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PLC-gamma, PLC-beta, DAG, IP3, Serotonin extracellular region, Insulin, G-protein alpha-q/11,, 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 [1], [2].

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) ) [1].

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 [1].

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 [3].


  1. Santagata S, Boggon TJ, Baird CL, Gomez CA, Zhao J, Shan WS, Myszka DG, Shapiro L
    G-protein signaling through tubby proteins. Science 2001 Jun 15;292(5524):2041-50
  2. Ikeda A, Nishina PM, Naggert JK
    The tubby-like proteins, a family with roles in neuronal development and function. Journal of cell science 2002 Jan 1;115(Pt 1):9-14
  3. Kapeller R, Moriarty A, Strauss A, Stubdal H, Theriault K, Siebert E, Chickering T, Morgenstern JP, Tartaglia LA, Lillie J
    Tyrosine phosphorylation of tub and its association with Src homology 2 domain-containing proteins implicate tub in intracellular signaling by insulin. The Journal of biological chemistry 1999 Aug 27;274(35):24980-6