Mayoral-Varo Victor, Jiménez Lucía, Link Wolfgang
Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain.
Cancers (Basel). 2021 May 30;13(11):2701. doi: 10.3390/cancers13112701.
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.
TRIBbles假激酶家族由TRIB1、TRIB2、TRIB3和STK40组成，尽管在进化上保守，但它们具有独特的特征。TRIBbles家族成员的表达具有背景和细胞区室依赖性。例如，TRIB1和TRIB2在脊椎动物细胞中具有强大的致癌活性。自从将TRIBbles蛋白鉴定为多种信号通路的调节因子以来，最近的研究将它们的表达与包括癌症在内的几种病理情况联系起来。TRIBbles蛋白作为参与泛素-蛋白酶体降解系统的蛋白质衔接子，因为它们在底物和E3连接酶之间架起了桥梁。在TRIB家族成员中，TRIB2是该家族最原始的成员。TRIB2参与C/EBPα、β-连环蛋白和TCF4的蛋白质稳态调节。另一方面，TRIB2与参与细胞存活、增殖和免疫反应的MAPKK、AKT和NFkB蛋白相互作用。在这里，我们综述了TRIB2结构和信号传导的特征及其在许多癌症亚型中的作用，重点是TRIB2在黑色素瘤、白血病和胶质母细胞瘤治疗耐药中的功能。TRIB2表达与化疗耐药之间的有力证据为靶向TRIB2提供了一个有吸引力的机会。
