TUBBY

The tubby strain of obese mice provides one of the few defined models for adult-onset obesity.   The tubby gene, which is highly expressed in the paraventricular nucleus of the hypothalamus and several other brain regions, was identified by isolating the genetic locus that transmits this autosomal recessive obesity syndrome.   Tubby mice have a naturally occurring splice site mutation at the junction of the 3' coding exon.   Targeted deletion of the tubby gene results in a phenotype identical to that of the naturally occurring mutants, indicating that the tubby obesity syndrome indeed arises from a loss of function.      The tubby protein is a member of a homologous family with four members (tubby and TULPs 1-3) encoded in the human genome and with others present in various multicellular organisms.   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.   Mutation of the tubby-like protein 1 gene TULP1 is the genetic origin of human retinitis pigmentosa type 14 (RP-14).   Mapping mutations from RP-14 patients onto the tubby C-terminal domain structure outlines a long positively charged groove implicated in DNA binding.   Tubby proteins also include N-terminal regions that, in their primary sequence, resemble activation domains from known transcription factors.   While the N-terminal domain of tubby can activate transcription of reporter constructs when fused to GAL4, potential targets of transcriptional regulation by tubby have not yet been identified.   Furthermore, little is known about signaling pathways regulating the function of tubby.      Genetic and physiological studies have revealed a host of signaling molecules that play critical roles in the neuroendocrine regulation of body weight.   These molecules include an abundance of neuropeptides and neurotransmitters, and their G protein coupled receptors (GPCRs) expressed in the hypothalamus.   GPCRs are among the primary cellular sensors implicated in systemic energy homeostasis.   Nonetheless, intracellular components of these GPCR signaling systems specifically relevant to function in weight regulation have not yet been identified.      We have shown that tubby, a molecule for which loss of function leads to obesity, serves as a downstream effector of GPCRs that signal through the Gq subclass of G proteins.   Tubby is anchored to the plasma membrane through binding phosphatidylinositol 4,5-bis-phosphate [PtdIns(4,5)P2].   Gq, but neither other G proteins nor G subunits, releases tubby from the plasma membrane through phospholipase C- mediated hydrolysis of PtdIns(4,5)P2, which results in tubby translocation to the nucleus.   Efficient nuclear translocation can be induced by activation of Gq-coupled receptors, including the serotonin receptor 5HT2c.   These data suggest that tubby - and other tubby-like proteins - may provide a direct link between G protein coupled receptor signaling and the regulation of gene expression.   Publications   Science 2001 Jun 15;292(5524):2041-50 G-Protein Signaling Through Tubby Proteins. Santagata S, Boggon TJ, Baird CL, Gomez CA, Zhao J, Shan WS, Myszka DG Shapiro L on-line    pdf   Science 1999 Dec 10;286(5447):2119-25 Implication of tubby proteins as transcription factors by structure-based functional analysis. Boggon TJ, Shan WS, Santagata S, Myers SC, Shapiro L on-line    pdf