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CARMA3: A novel scaffold protein in regulation of NF-κB activation and diseases
1Jiyuan Sun, Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, TX 77030, United States.
Abstract:
CARD recruited membrane associated protein 3 (CARMA3) is a novel scaffold protein. It belongs to the CARMA protein family, and is known to activate nuclear factor (NF)-κB. However, it is still unknown which receptor functions upstream of CARMA3 to trigger NF-κB activation. Recently, several studies have demonstrated that CARMA3 serves as an indispensable adaptor protein in NF-κB signaling under some G protein-coupled receptors (GPCRs), such as lysophosphatidic acid (LPA) receptor and angiotensin (Ang) II receptor. Mechanistically, CARMA3 recruits its essential downstream molecules Bcl10 and MALT1 to form the CBM (CARMA3-Bcl10-MALT1) signalosome whereby it triggers NF-κB activation. GPCRs and NF-κB play pivotal roles in the regulation of various cellular functions, therefore, aberrant regulation of the GPCR/NF-κB signaling axis leads to the development of many types of diseases, such as cancer and atherogenesis. Recently, the GPCR/CARMA3/NF-κB signaling axis has been confirmed in these specific diseases and it plays crucial roles in the pathogenesis of disease progression. In ovarian cancer cell lines, knockdown of CARMA3 abolishes LPA receptor-induced NF-κB activation, and reduces LPA-induced ovarian cancer invasion. In vascular smooth cells, downregulation of CARMA3 substantially impairs Ang-II-receptor-induced NF-κB activation, and in vivo studies have confirmed that Bcl10-deficient mice are protected from developing Ang-II-receptor-induced atherosclerosis and aortic aneurysms. In this review, we summarize the biology of CARMA3, describe the role of the GPCR/CARMA3/NF-κB signaling axis in ovarian cancer and atherogenesis, and speculate about the potential roles of this signaling axis in other types of cancer and diseases. With a significant increase in the identification of LPA- and Ang-II-like ligands, such as endothelin-1, which also activates NF-κB via CARMA3 and contributes to the development of many diseases, CARMA3 is emerging as a novel therapeutic target for various types of cancer and other diseases.
Insights
CARD-recruited membrane associated protein 3 (CARMA3) is crucial for G protein-coupled receptor signaling and NF-κB activation. This pathway is implicated in diseases like cancer and atherosclerosis, highlighting CARMA3 as a potential therapeutic target.
Area of Science:
- Molecular Biology
- Cell Signaling
- Disease Pathogenesis
Background:
- CARD-recruited membrane associated protein 3 (CARMA3) is a scaffold protein that activates nuclear factor (NF)-κB.
- G protein-coupled receptors (GPCRs) like LPA and Ang II receptor utilize CARMA3 in NF-κB signaling.
- Aberrant GPCR/NF-κB signaling contributes to diseases such as cancer and atherosclerosis.
Purpose of the Study:
- To review the biology of CARMA3 and its role in the GPCR/CARMA3/NF-κB signaling axis.
- To explore the involvement of this axis in ovarian cancer and atherogenesis.
- To speculate on the broader implications of this pathway in other diseases and its potential as a therapeutic target.
Main Methods:
- Literature review summarizing existing studies on CARMA3 and its signaling pathways.
- Analysis of CARMA3's role in NF-κB activation downstream of specific GPCRs.
- Examination of experimental evidence from cancer cell lines and animal models.
Main Results:
- CARMA3 forms the CBM signalosome (CARMA3-Bcl10-MALT1) to trigger NF-κB activation.
- CARMA3 is essential for LPA receptor-induced NF-κB activation and ovarian cancer invasion.
- CARMA3 mediates Ang-II-receptor-induced NF-κB activation; Bcl10 deficiency protects against atherosclerosis and aneurysms.
Conclusions:
- The GPCR/CARMA3/NF-κB signaling axis plays a critical role in ovarian cancer and atherogenesis.
- CARMA3 is a key mediator linking GPCRs to NF-κB activation in disease pathogenesis.
- CARMA3 represents a promising therapeutic target for various cancers and other diseases.
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