The Critical Role of TRIB2 in Cancer and Therapy Resistance

Abstract

The Tribbles pseudokinases family consists of TRIB1, TRIB2, TRIB3 and STK40 and, although evolutionarily conserved, they have distinctive characteristics. Tribbles members are expressed in a context and cell compartment-dependent manner. For example, TRIB1 and TRIB2 have potent oncogenic activities in vertebrate cells. Since the identification of Tribbles proteins as modulators of multiple signalling pathways, recent studies have linked their expression with several pathologies, including cancer. Tribbles proteins act as protein adaptors involved in the ubiquitin-proteasome degradation system, as they bridge the gap between substrates and E3 ligases. Between TRIB family members, TRIB2 is the most ancestral member of the family. TRIB2 is involved in protein homeostasis regulation of C/EBPα, β-catenin and TCF4. On the other hand, TRIB2 interacts with MAPKK, AKT and NFkB proteins, involved in cell survival, proliferation and immune response. Here, we review the characteristic features of TRIB2 structure and signalling and its role in many cancer subtypes with an emphasis on TRIB2 function in therapy resistance in melanoma, leukemia and glioblastoma. The strong evidence between TRIB2 expression and chemoresistance provides an attractive opportunity for targeting TRIB2.

TRIB2 regulates the expression of miR‑33a‑5p through the ERK/c‑Fos pathway to affect the imatinib resistance of chronic myeloid leukemia cells

“…Tribbles pseudokinase 2 (TRIB2) is a member of the tribbles family ( 8 ). TRIB2 includes an N-terminal domain, a C-terminal domain and a central pseudokinase domain.…”

Comprehensive Profiling of Mammalian Tribbles Interactomes Implicates TRIB3 in Gene Repression

“…While not previously described as binding partners, the mTOR regulatory subunits RICTOR and RAPTOR were also detected in the TRIB2 interactome ( Figure 1 C). Previous studies have shown, however, that TRIB2 regulates mTOR signaling [ 42 , 43 ]. Interactions that have not been described earlier included the interaction between TRIB3 and the mitochondrial transporter TIM-TOM complex, a complex found in the mitochondrial membrane that transports proteins into the inner membrane of the mitochondria [ 44 ].…”

Modulating undruggable targets to overcome cancer therapy resistance

“…Tribbles 2 (TRIB2) is a cancer-associated pseudokinase with a diverse interactome, includes MEK1 and AKT as binding partners. There is substantial evidence that human TRIB2 promotes survival and drug resistance in solid tumors (Ferreira et al, 2021;Mayoral-Varo et al, 2021) and hematological cancers (Stein et al, 2015) and therefore is of interest as a therapeutic target. The TRIB2 destabilizing agent afatinib (34) caused rapid TRIB2 degradation in human AML cancer cells (Foulkes et al, 2018) providing the proof of concept for the druggability of the TRIB2 oncoprotein.…”