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FB2026_01
,
released March 12, 2026
This report describes the disease model 'insulin pathway effects, TRIB-related'. Members of the Tribble (TRIB) family are kinase-like proteins that have multiple and varied roles in cell signaling and tissue homeostasis. The human TRIB3 gene, one of three human Tribble genes, has been implicated as a susceptibility locus for type 2 diabetes. There is a single Tribble gene in Drosophila, Dmel\trbl, for which RNAi-targeting constructs and alleles caused by insertional mutagenesis have been generated. Dmel\trbl is also orthologous to human TRIB1 and TRIB2.
The human TRIB3 gene has not been introduced into flies. The mouse gene Mmus\Trib3 has been introduced into flies and has been characterized in the context of the Q84R polymorphism (see below).
In flies, RNAi-effected knockdown of trbl in the fat body results in increased cell size, delays the onset of pupation, and increases levels of circulating triglycerides; overexpression of trbl results in the opposite phenotypes. Dmel\trbl was initially characterized in a screen for genes that interact with Dmel\Akt; see the human disease model report 'diabetes mellitus type 2, susceptibility to, AKT-related' (FBhh0000170). Additional genetic and physical interactions of Dmel\trbl have been described; see below and in the trbl gene report.
A polymorphism in the TRIB3 gene in human (Q84R) has been associated with a predisposition to type 2 diabetes and related diseases. The TRIB3 gene is unique in typically having a glutamine at this position; most metazoan TRIB genes, including the Dmel\trbl gene, have an arginine. The two cases, of a glutamine vs. an arginine at this position, have been characterized and compared in the fly. See the 'Disease-Implicate Variants' table, below.
[updated Aug. 2021 by FlyBase; FBrf0222196]
Diseases associated with TRIB3 include Diabetes Mellitus, Noninsulin-Dependent. [Gene Cards, TRIB3; 2018.06.26]
TRIB3 overactivity, due to TRIB3 overexpression or to the Q84R genetic polymorphism, with R84 being a gain-of-function variant, appears to be involved in shaping the risk of insulin resistance, T2DM, and cardiovascular disease (Prudente et al., 2012; pubmed:22577090).
Members of the TRIB family are kinase-like proteins that have diverse roles in cell signaling, tissue homeostasis, and cancer. TRIB proteins share three motifs: a divergent kinase region (Trib domain); a COP1 site used to direct key target proteins to the proteasome for degradation; and a MEK1 site that binds and modulates MAPKK kinase activity. Although they have no DNA-binding capacity themselves, in the nucleus TRIBs are tightly associated with target promoters and exhibit transcriptional co-activator and co-repressor functions (Dobens and Bouyain, 2012; pubmed:22711497; FBrf0218858).
Many to one: 3 human to 1 Drosophila; the human genes are TRIB1, TRIB2, and TRIB3.
Many to one: 3 human to 1 Drosophila; the human genes are TRIB1, TRIB2, and TRIB3.
Many to one: 3 human to 1 Drosophila; the human genes are TRIB1, TRIB2, and TRIB3.
Moderate- to high-scoring ortholog of human TRIB1, TRIB2, and TRIB3 (1 Drosophila to 3 human). Dmel\trbl shares 33-36% identity and 47-52% similarity with the human genes.