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].
References:
- Santagata S, Boggon TJ, Baird CL, Gomez CA, Zhao J, Shan WS, Myszka DG, Shapiro L
G-protein signaling through tubby proteins.
Science (New York, N.Y.) 2001 Jun 15;292(5524):2041-50
- 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
- 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
