The Mammalian Tribbles Homolog TRIB3, Glucose Homeostasis, and Cardiovascular Diseases
Sabrina Prudente,Giorgio Sesti,Assunta Pandolfi,Francesco Andreozzi,Agostino Consoli,Vincenzo Trischitta +5 more
TLDR
Studies on TRIB3 have unraveled new molecular mechanisms underlying metabolic and cardiovascular abnormalities, and additional investigations are needed to verify whether such acquired knowledge will be relevant for improving care delivery to patients with metabolic andiovascular alterations.Abstract:
Insulin signaling plays a physiological role in traditional insulin target tissues controlling glucose homeostasis as well as in pancreatic β-cells and in the endothelium. Insulin signaling abnormalities may, therefore, be pathogenic for insulin resistance, impaired insulin secretion, endothelial dysfunction, and eventually, type 2 diabetes mellitus (T2DM) and cardiovascular disease. Tribbles homolog 3 (TRIB3) is a 45-kDa pseudokinase binding to and inhibiting Akt, a key mediator of insulin signaling. Akt-mediated effects of TRIB3 in the liver, pancreatic β-cells, and skeletal muscle result in impaired glucose homeostasis. TRIB3 effects are also modulated by its direct interaction with other signaling molecules. In humans, TRIB3 overactivity, due to TRIB3 overexpression or to Q84R genetic polymorphism, with R84 being a gain-of-function variant, may be involved in shaping the risk of insulin resistance, T2DM, and cardiovascular disease. TRIB3 overexpression has been observed in the liver, adipose tissue, skeletal muscle, and pancreatic β-cells of individuals with insulin resistance and/or T2DM. The R84 variant has also proved to be associated with insulin resistance, T2DM, and cardiovascular disease. TRIB3 direct effects on the endothelium might also play a role in increasing the risk of atherosclerosis, as indicated by studies on human endothelial cells carrying the R84 variant that are dysfunctional in terms of Akt activation, NO production, and other proatherogenic changes. In conclusion, studies on TRIB3 have unraveled new molecular mechanisms underlying metabolic and cardiovascular abnormalities. Additional investigations are needed to verify whether such acquired knowledge will be relevant for improving care delivery to patients with metabolic and cardiovascular alterations.read more
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Loss-of-Function Mutations in APPL1 in Familial Diabetes Mellitus
Sabrina Prudente,Prapaporn Jungtrakoon,Prapaporn Jungtrakoon,Antonella Marucci,Ornella Ludovico,Patinut Buranasupkajorn,Patinut Buranasupkajorn,Tommaso Mazza,Timothy Hastings,Teresa Milano,Eleonora Morini,Luana Mercuri,Diego Bailetti,Christine Mendonca,Federica Alberico,Giorgio Basile,Marta Romani,Elide Miccinilli,Antonio Pizzuti,Massimo Carella,Fabrizio Barbetti,Stefano Pascarella,Piero Marchetti,Vincenzo Trischitta,Rosa Di Paola,Alessandro Doria,Alessandro Doria +26 more
TL;DR: Two loss-of-function mutations in the gene for the Adaptor Protein, Phosphotyrosine Interaction, PH domain, and leucine zipper containing 1 are reported to confirm the critical role of APPL1 in glucose homeostasis.
Journal ArticleDOI
TRIB3 supports breast cancer stemness by suppressing FOXO1 degradation and enhancing SOX2 transcription
Jin-mei Yu,Wei Sun,Zhen-he Wang,Xiao Liang,Fang Hua,Ke Li,Xiaoxi Lv,Xiaowei Zhang,Yuying Liu,Jiao-jiao Yu,Shan-Shan Liu,Shuang Shang,Feng Wang,Zhao-na Yang,Chen-xi Zhao,Xue-ying Hou,Pingping Li,Bo Huang,Bing Cui,Zhuo-Wei Hu +19 more
TL;DR: It is reported that expression of the pseudokinase Tribble 3 (TRIB3) positively associates with breast cancer stemness and progression and is a potential therapeutic strategy against TRIB3-overexpressed breast cancer.
Journal ArticleDOI
TRB3 links insulin/IGF to tumour promotion by interacting with p62 and impeding autophagic/proteasomal degradations.
Fang Hua,Ke Li,Jiao jiao Yu,Xiao Xi Lv,Jun Yan,Xiaowei Zhang,Wei Sun,Heng Lin,Shuang Shang,Feng Wang,Bing Cui,Rong Mu,Bo Huang,Jian Dong Jiang,Zhuo-Wei Hu +14 more
TL;DR: A previously unrecognized tumour-promoting mechanism for stress protein TRB3 is reported, which mediates a reciprocal antagonism between autophagic and proteasomal degradation systems and connects insulin/IGF to malignant promotion.
Journal ArticleDOI
Mitochondria Retrograde Signaling and the UPRmt: Where Are We in Mammals?
TL;DR: Whether the UPRmt is relevant to mitochondrial homeostasis in mammals is addressed and the putative role of integrated stress response (ISR) activation in response to the inhibition of mtDNA expression and/or accumulation of mitochondrial mis/unfolded proteins is analyzed.
Journal ArticleDOI
Molecular Mechanism of CCAAT-Enhancer Binding Protein Recruitment by the TRIB1 Pseudokinase.
James M. Murphy,James M. Murphy,Yoshio Nakatani,Sam A. Jamieson,Weiwen Dai,Weiwen Dai,Isabelle S Lucet,Isabelle S Lucet,Peter D. Mace +8 more
TL;DR: The first crystal structure of a Tribbles protein is presented, which reveals a catalytically inactive TRIB1 pseudokinase domain with a unique adaptation in the αC helix and the substrate-recognition sequence within C/EBPα, which is evolutionarily conserved in C-EBP transcription factors.
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