The functionally diverse roles of tribbles.

Tribbles are members of the pseudokinase family of proteins, with no associated kinase activity detectable to date. As tribbles appear not to function as kinases, there has been debate surrounding their functional classification. Tribbles have been proposed to function as adaptor molecules facilitating degradation of their target proteins. Tribbles have also been proposed to mediate signalling changes to MAPK (mitogen-activated protein kinase) cascades and also to function as decoy kinases interfering with the activity of known kinases. The present review discusses the functionally divergent roles of tribbles as molecular adaptors mediating degradation, changes to signalling cascades and action as decoy kinases.

Elevated TRIB2 with NOTCH1 activation in paediatric/adult T-ALL.

TRIB2 is a potent oncogene, elevated in a subset of human acute myeloid leukaemias (AML) with a mixed myeloid/lymphoid phenotype and NOTCH1 mutations. Although rare in AML, activating NOTCH1 mutations occur in 50% of all T cell acute lymphoblastic leukaemias (T-ALL). TRIB2 is a NOTCH1 target gene that functions in the degradation of key proteins and modulation of MAPK signalling pathways, implicated in haematopoietic cell survival and proliferation. This study showed that TRIB2 expression level is highest in the lymphoid compartment of normal haematopoietic cells, specifically in T cells. Analysis of TRIB2 expression across 16 different subtypes of human leukaemia demonstrated that TRIB2 expression was higher in ALL phenotypes versus all other phenotypes including AML, chronic lymphocytic leukaemia (CLL), myelodysplastic syndrome (MDS) and chronic myeloid leukaemia (CML). A T cell profile was distinguished by high TRIB2 expression in normal and malignant haematopoiesis. High TRIB2 expression was seen in T-ALL with normal karyotype and correlated with NOTCH signalling pathways. High TRIB2 expression correlated with NOTCH1/FBXW7 mutations in a paediatric T-ALL cohort, strongly linking NOTCH1 activation and high TRIB2 expression in paediatric T-ALL. The relationship between TRIB2 and T cell signalling pathways uniquely identifies leukaemia subtypes and will be useful in the advancement of our understanding of T cell and ALL biology.