Developmental roles of tribbles protein family members

Abstract

The gene tribbles (trbl), identified 12 years ago in genetic screens for mutations that control both cell division and cell migration during embryonic Drosophila development, is the founding member of the Tribbles (Trib) family of kinase-like proteins that have diverse roles in cell signaling, tissue homeostasis, and cancer. Trib proteins share three motifs: (1) a divergent kinase region (Trib domain) with undetermined catalytic activity, (2) a COP1 site used to direct key target proteins to the proteosome for degradation, and (3) a MEK1 site that binds and modulates MAPKK kinase activity. The notion that Tribs act as scaffolding proteins to balance signaling levels in multiple pathways retains an attractive simplicity, but given recent data showing that divergent kinases act by means of novel catalytic mechanisms, the enzymatic activity of Tribs remains untested. Here, we focus on the role of Tribs during development. Developmental analysis of Drosophila trbl phenotypes reveals tissue-specific, sometimes contradictory roles. In mammals, multiple Trib isoforms exhibit overlapping and tissue-specific functions. Recent data indicate the mechanism of Trib activity is conserved and requires the Trib domain. Finally, we discuss the connections between Tribs in disease and cancer that have implications for their normal roles during organogenesis.

Regulation of Trib2 by an E2F1-C/EBPα feedback loop in AML cell proliferation

“…1 Trib proteins' diverse roles include cell proliferation, survival, motility, and metabolism. 2 There is a strong correlation between dysregulated Trib2 expression and acute myeloid and lymphoid leukemia (AML and ALL). Elevated Trib2 expression associates with a specific subset of AML characterized by dysregulated CCAAT enhancer-binding protein a (C/EBPa) and with T-cell ALL (T-ALL), both linked with NOTCH1 mutations.…”

TRIB2 and the ubiquitin proteasome system in cancer

“…The first connections between TRIB and protein degradation functions were identified in drosophila, where drosophila tribbles was shown to promote degradation of its targets; String (homologous of the mammalian CDC25 phosphatase, positive regulator of cell cycle progression) and slow border cells (Slbo) (promoter of cell migration and homologous of the human C/EBP) [20] . The members of the C/EBP family of transcription factors are involved in regulation of differentiation in many tissues and control proliferation through interaction with cell cycle proteins.…”

Tribbles role in reproduction

“…Therefore they may be unable to effectively phosphorylate their target proteins [3]. Hence, it is believed that TRIB may be working with a wide range of targets as scaffold proteins and controlling various signalling pathways [1]. Scaffold/adaptor proteins smooth the flow of signals by helping with translocation and facilitate proximity of different components of a signalling cascade.…”

“…Mutation in the tribbles genes gives the fruit fly a look reminiscent to the fictitious creatures in this series. A rapidly growing body of literature highlights the involvement of TRIB proteins in different physiological and pathological processes ranging from cancer to immune system regulation [1,2]. In recent years, we have gathered evidence that TRIB proteins may have an effect on reproductive processes, too [Basatvat Shaghayegh, Carter Deborah Angela Louise, Kiss-Toth Endre and Fazeli Alireza, unpublished work].…”