Pseudokinases are catalytically inactive proteins in the human genome that lack the ability to transfer phosphate from ATP to their substrates. The Tribbles family of pseudokinases contains three members: Tribbles 1, 2, and 3. Tribbles 1 has recently gained importance because of its involvement in various diseases, including cancer. It acts as a scaffolding protein that brings about the degradation of its substrate proteins, such as C/EBPα/β, MLXIPL, and RAR/RXRα, among others, via the ubiquitin proteasome system. It also serves as an adapter protein, which sequesters different protein molecules and activates their downstream signaling, leading to processes, such as cell survival, cell proliferation, and lipid metabolism. It has been implicated in cancers such as AML, prostate cancer, breast cancer, CRC, HCC, and glioma, where it activates oncogenic signaling pathways such as PI3K-AKT and MAPK and inhibits the anti-tumor function of p53. TRIB1 also causes treatment resistance in cancers such as NSCLC, breast cancer, glioma, and promyelocytic leukemia. All these effects make TRIB1 a potential drug target. However, the lack of a catalytic domain renders TRIB1 “undruggable”, but knowledge about its structure, conformational changes during substrate binding, and substrate binding sites provides an opportunity to design small-molecule inhibitors against specific TRIB1 interactions.
伪激酶是人类基因组中催化失活的蛋白质，缺乏将磷酸基团从ATP转移至底物的能力。Tribbles家族伪激酶包含三个成员：Tribbles 1、2和3。近年来Tribbles 1因参与包括癌症在内的多种疾病过程而备受关注。它作为支架蛋白通过泛素蛋白酶体系统介导C/EBPα/β、MLXIPL及RAR/RXRα等底物蛋白的降解；同时作为衔接蛋白可隔离不同蛋白分子并激活其下游信号传导，从而调控细胞存活、增殖及脂质代谢等过程。该蛋白在急性髓系白血病、前列腺癌、乳腺癌、结直肠癌、肝细胞癌及胶质瘤等多种癌症中发挥作用，通过激活PI3K-AKT和MAPK等致癌信号通路并抑制p53的抗肿瘤功能促进肿瘤发展。TRIB1还与非小细胞肺癌、乳腺癌、胶质瘤及早幼粒细胞白血病等癌症的治疗耐药性相关。这些生物学效应使TRIB1成为潜在药物靶点。尽管其催化结构域的缺失导致传统靶向策略受限，但对其三维结构、底物结合过程中的构象变化及结合位点的深入研究，为设计针对特定TRIB1相互作用的小分子抑制剂提供了新的契机。
“Oh, Dear We Are in Tribble”: An Overview of the Oncogenic Functions of Tribbles 1
肿瘤(癌症)患者之家