Last update 01 Nov 2024

TRIM4

Last update 01 Nov 2024

Basic Info

Synonyms

E3 ubiquitin-protein ligase TRIM4, RING finger protein 87, RING-type E3 ubiquitin transferase TRIM4

+ [4]

Introduction

E3 ubiquitin-protein ligase. Mediates 'Lys-63'-linked polyubiquitination of the innate immune receptor RIGI, this linkage doesn't lead to proteasomal degradation but seems to enhance IFN induction.

Drugs associated with TRIM4

PJ2-02

Target

TRIM4

Mechanism

TRIM4 modulators

Active Org.

StemRIM, Inc.

Originator Org.

StemRIM, Inc.

Active Indication

Soft Tissue Injuries

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with TRIM4

100 Translational Medicine associated with TRIM4

0 Patents (Medical) associated with TRIM4

Literatures (Medical) associated with TRIM4

01 Sep 2024·Cell Reports

The TRIM4 E3 ubiquitin ligase degrades TPL2 and is modulated by oncogenic KRAS

Article

Author: Dodhiawala, Paarth B ; Adhikari, Hema ; Lim, Kian-Huat ; Townsend, Reid ; Dodhiawala, Paarth B. ; Geng, Yutong ; Bansod, Sapana ; Grierson, Patrick M ; Grierson, Patrick M. ; Held, Jason M ; Held, Jason M. ; Liu, Peng ; Bulle, Ashenafi ; Li, Lin

Loss-of-function mutations in the C terminus of TPL2 kinase promote oncogenesis by impeding its proteasomal degradation, leading to sustained protein expression. However, the degradation mechanism for TPL2 has remained elusive. Through proximity-dependent biotin identification (BioID), we uncovered tripartite motif-containing 4 (TRIM4) as the E3 ligase that binds and degrades TPL2 by polyubiquitination of lysines 415 and 439. The naturally occurring TPL2 mutants R442H and E188K exhibit impaired TRIM4 binding, enhancing their stability. We further discovered that TRIM4 itself is stabilized by another E3 ligase, TRIM21, which in turn is regulated by KRAS. Mutant KRAS recruits RNF185 to degrade TRIM21 and subsequently TRIM4, thereby stabilizing TPL2. In the presence of mutant KRAS, TPL2 phosphorylates and degrades GSK3β, resulting in β-catenin stabilization and activation of the Wnt pathway. These findings elucidate the physiological mechanisms regulating TPL2 and its exploitation by mutant KRAS, underscoring the need to develop TPL2 inhibitors for KRAS-mutant cancers.

01 Jan 2024·Journal of Thoracic Oncology

MET Fusions in NSCLC: Clinicopathologic Features and Response to MET Inhibition

Article

Author: Kobe, Carsten ; Eisert, Anna ; Michels, Sebastian ; Schaufler, Diana ; Fischer, Rieke N ; Riedel, Richard ; Pappesch, Roberto ; Scheel, Andreas H ; Ruge, Lea ; Wagener-Ryczek, Svenja ; Büttner, Reinhard ; Wolf, Jürgen ; Fassunke, Jana ; Ihle, Michaela A ; Heydt, Carina ; Siemanowski, Janna ; Scharpenseel, Heather ; Bunck, Anne ; Scheffler, Matthias ; Merkelbach-Bruse, Sabine ; John, Felix ; Nogova, Lucia ; Keil, Felix ; Rehker, Jan

INTRODUCTIONMET fusions have been described only rarely in NSCLC. Thus, data on patient characteristics and treatment response are limited. We here report histopathologic data, patient demographics, and treatment outcome including response to MET tyrosine kinase inhibitor (TKI) therapy in MET fusion-positive NSCLC.METHODSPatients with NSCLC and MET fusions were identified mostly by RNA sequencing within the routine molecular screening program of the national Network Genomic Medicine, Germany.RESULTSWe describe a cohort of nine patients harboring MET fusions. Among these nine patients, two patients had been reported earlier. The overall frequency was 0.29% (95% confidence interval: 0.15-0.55). The tumors were exclusively adenocarcinoma. The cohort was heterogeneous in terms of age, sex, or smoking status. We saw five different fusion partner genes (KIF5B, TRIM4, ST7, PRKAR2B, and CAPZA2) and several different breakpoints. Four patients were treated with a MET TKI leading to two partial responses, one stable disease, and one progressive disease. One patient had a BRAF V600E mutation as acquired resistance mechanism.CONCLUSIONSMET fusions are very rare oncogenic driver events in NSCLC and predominantly seem in adenocarcinomas. They are heterogeneous in terms of fusion partners and breakpoints. Patients with MET fusion can benefit from MET TKI therapy.

01 Jan 2024·Applied Biochemistry and Biotechnology

TRIM4 Expression Related to Malignant Progression and Cisplatin Resistance in Osteosarcoma

Article

Author: Li, Yan ; Zhang, Huawu ; Wang, Dong ; Liu, Zijin ; Gao, Jie

Osteosarcoma (OS) is a high-grade intraosseous malignancy. Twenty to thirty percent of OS patients react poorly to standard therapy with a combination of surgical resection and chemotherapy. It is necessary to find molecules that play an important role in this. This study explored the role of TRIM4 in OS chemotherapy sensitivity and malignant progression. The expression of TRIM4 in OS tissues and cells was examined by RT-qPCR, immunohistochemical staining, and western blot. Specific siRNA was transfected into U2-OS and SAOS2 cells to target TRIM4. Cell biological behavior was examined by CCK-8, Transwell, and flow cytometry experiments. Cisplatin-resistant SAOS2 (SAOS2-Cis-R) cells were established, and the effect of TRIM4 expression on the cisplatin response of SAOS2 cells was tested. Knockdown of TRIM4 significantly inhibited the proliferation, migration, and invasion of U2-OS and SAOS2 cells and induced apoptosis. TRIM4 expression was significantly higher in chemotherapy-resistant OS tissues compared to chemotherapy-sensitive OS tissues. Furthermore, the expression of TRIM4 in SAOS2-Cis-R cells was significantly increased compared to parental SAOS2 cells. Moreover, overexpression of TRIM4 enhanced cisplatin resistance in parental SAOS2 cells, while the downregulation of TRIM4 expression enhanced cisplatin sensitivity of SAOS2-Cis-R cells. High TRIM4 expression might be associated with malignant progression and poor response to chemotherapy response of OS. Targeting TRIM4 may be beneficial for OS treatment or combination therapy.

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