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Last update 23 Jan 2025

TAB1

Last update 23 Jan 2025

Basic Info

Synonyms

MAP3K7IP1, Mitogen-activated protein kinase kinase kinase 7-interacting protein 1, TAB1

+ [4]

Introduction

Key adapter protein that plays an essential role in JNK and NF-kappa-B activation and proinflammatory cytokines production in response to stimulation with TLRs and cytokines (PubMed:22307082, PubMed:24403530). Mechanistically, associates with the catalytic domain of MAP3K7/TAK1 to trigger MAP3K7/TAK1 autophosphorylation leading to its full activation (PubMed:10838074, PubMed:25260751). Similarly, associates with MAPK14 and triggers its autophosphorylation and subsequent activation (PubMed:11847341, PubMed:29229647). In turn, MAPK14 phosphorylates TAB1 and inhibits MAP3K7/TAK1 activation in a feedback control mechanism (PubMed:14592977). Plays also a role in recruiting MAPK14 to the TAK1 complex for the phosphorylation of the TAB2 and TAB3 regulatory subunits (PubMed:18021073).

Drugs associated with TAB1

ALF-1

Target

MAPK x TAB1 x TLR4

Mechanism

MAPKs inhibitors [+2]

Active Org.-

Originator Org.

Shenyang Pharmaceutical University

Active Indication-

Inactive Indication

Liver Cirrhosis

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with TAB1

100 Translational Medicine associated with TAB1

0 Patents (Medical) associated with TAB1

530

Literatures (Medical) associated with TAB1

01 Mar 2025·Current Molecular Medicine

Explore on the Mechanism of miRNA-146a/TAB1 in the Regulation of Cellular Apoptosis and Inflammation in Ulcerative Colitis Based on NF-κB Pathway

Article

Author: Duan, Yanan ; Du, Yulin ; Xia, Xiaoying ; Guo, Shujun ; Ding, Zebang ; Yang, Qian ; Hua, Mengqing ; Li, Yao ; Ma, Hua ; Fang, Fang ; Huo, Qi ; Tian, Wenjing ; Yuan, Hui ; Ma, Zhigang ; Han, Xue

Objective::Ulcerative colitis (UC) is a chronic non-specific inflammatory disease of the rectum and colon with unknown etiology. A growing number of evidence suggest that the pathogenesis of UC is related to excessive apoptosis and production of inflammatory cytokines. However, the functions and molecular mechanisms associated with UC remain unclear.Materials and Methods:The in vivo and in vitro models of UC were established in this study. MiRNA or gene expression was measured by qRT-PCR assay. ELISA, CCK-8, TUNEL, and flow cytometry assays were applied for analyzing cellular functions. The interactions between miR-146a and TAB1 were verified by luciferase reporter and miRNA pull-down assays.Results::MiR-146a was obviously increased in UC patients, DSS-induced colitis mice, and TNF-ɑ-induced YAMC cells, when compared to the corresponding controls. MiR- 146a knockdown inhibited the inflammatory response and apoptosis in DSS-induced colitis mice and TNF-ɑ-induced YAMC cells. Mechanistically, we found that TAB1 was the target of miR-146a and miR-146a knockdown suppressed the activation of NF-κB pathway in UC. More importantly, TAB1 could overturn the inhibitory effect of antagomiR-146a on cell apoptosis and inflammation in UC.Conclusion::MiR-146a knockdown inhibited cell apoptosis and inflammation via targeting TAB1 and suppressing NF-κB pathway, suggesting that miR-146a may be a new therapeutic target for UC treatment

01 Jan 2025·Cancer Research Communications

Preclinical Development of Tuspetinib for the Treatment of Acute Myeloid Leukemia

Article

Author: Bejar, Raphael ; Howell, Stephen B. ; Jung, Seung Hyun ; Sonowal, Himangshu ; Sinha, Ranjeet ; Rice, William G. ; Byun, Joo-Yun

AbstractTuspetinib (TUS) is a well-tolerated, once daily, oral kinase inhibitor in clinical development for treatment of acute myeloid leukemia (AML). Nonclinical studies show that TUS targets key prosurvival kinases with IC50 values in the low nmol/L range, including SYK, wild-type (WT) and mutant forms of FLT3, mutant but not WT forms of KIT, RSK2, and TAK1–TAB1 kinases, and indirectly suppresses expression of MCL1. Oral TUS markedly extended survival in subcutaneously and orthotopically inoculated xenograft models of FLT3-mutant human AML, was well tolerated, and delivered enhanced activity when combined with venetoclax (VEN) or 5-azacytidine. In vitro, TUS demonstrated potent killing of AML lines [concentration needed to reduce the growth of treated cells to half that of untreated cells (GI50) = 1.3–5.2 nmol/L] and Ba/F3 cells expressing WT (GI50 = 9.1 nmol/L) or various mutant forms of FLT3 (GI50 = 2.5–56 nmol/L). In AML lines, the multikinase targeting capacity of TUS suppressed phosphorylation of SYK, FLT3, STAT5, MEK, ERK, AKT, mTOR, 4E-BP1, and S6K kinases. Cells selected for stable acquired resistance to TUS exhibited increased BAX and hypersensitivity to VEN (1900 fold), navitoclax, and MCL1 inhibitors. MV-4-11 FLT3-ITD clones expressing NRASG12D revealed that high-level expression of NRASG12D generated modest resistance to TUS and greater resistance to VEN, yet the TUS/VEN combination exhibited synergy in the NRASG12D AML model. Favorable preclinical safety and pharmacology properties, the efficacy of the TUS/VEN combination in a murine model, and the synthetic lethal vulnerability to VEN that accompanies TUS resistance provide the basis for exploration of the TUS/VEN combination in patients with relapsed or refractory AML.Significance:This article reports preclinical development of TUS, an oral kinase inhibitor currently in clinical development for treatment of AML. The article covers the studies of TUS activities on cellular targets and the nonclinical studies that supported the advancement of TUS to a phase I/II trial of TUS/VEN in refractory AML and a phase I/II trial of TUS/VEN/5-azacytidine in newly diagnosed patients with AML (NCT03850574).

01 Jan 2025·International Immunopharmacology

Progesterone suppresses rhinovirus-induced airway inflammation by inhibiting neutrophil infiltration and extracellular traps formation

Article

Author: Chen, Hengyu ; Huang, Feng-Ying ; Xie, Weijing ; Wu, Ri-Hong ; Dai, Shu-Zhen ; Tan, Guang-Hong ; Zheng, Wu-Ping ; Chen, Ming-Hui

BACKGROUNDThe process of NETosis is observed in a range of inflammatory conditions. Progesterone (P4) has been shown to alleviate inflammation caused by viral infections such as influenza and SARS-CoV-2. However, the precise molecular mechanisms responsible for this effect are not yet fully understood. Therefore, the present investigation aims to explore whether P4 can exert its anti-inflammatory properties by inhibiting NETosis and the related molecular pathways.METHODSAirway inflammation caused by rhinovirus serotype-1b (RV-1b) was induced in male BALB/c mice. The inflammation was assessed through histological examination and calculation of inflammatory cells present in the bronchoalveolar lavage fluid. Flow cytometry was used to analyze the inflammatory cells and NETotic neutrophils. Western blotting analysis was conducted to detect proteins associated with NETosis, inflammasome activation, and signaling. Furthermore, confocal microscopy was utilized to observe neutrophil extracellular trap (NET) structures in vivo tissues and in vitro neutrophils, neutrophil infiltration, and inflammasome formation.RESULTSThe administration of P4 proved to be an effective treatment for reducing airway inflammation and the production of NETs caused by RV-1b infection. The infection triggered the activation of NLRP3 inflammasomes in neutrophils, which led to the maturation of IL-1β and subsequent activation of both the NF-κB and p38 signaling pathways. The activation of NF-κB signaling resulted in the secretion of downstream chemokines CCL3 and IL-6, which led to an increase in neutrophil infiltration into the lung airways. Moreover, the activation of p38 signaling led to the generation of reactive oxygen species, resulting in NETosis. However, the administration of P4 inhibited the activation of the NLRP3 inflammasome, which subsequently led to the deactivation of both the IL-1β-NF-κB and IL-1β-p38 axes. As a result, there was a reduction in neutrophil infiltration and NETosis. Furthermore, TGF-β-activated kinase 1 (TAK1) was identified as an intermediary enzyme. P4 inhibits both the NF-κB and IL-1β-p38 pathways by suppressing the activity of TAK1.CONCLUSIONThe capacity of P4 to mitigate rhinovirus-induced airway inflammation is attributed to its ability to impede the infiltration of neutrophils and NETosis. As inflammation mediated by NETosis is widespread in diverse disorders, our findings propose that P4 could potentially function as a universal therapeutic agent in the management of such ailments.

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