Regulation of NF‐κB by the CARD proteins

Abstract

Summary: Scaffold proteins play pivotal roles in the regulation of signal transduction pathways by connecting upstream receptors to downstream effector molecules. During the last decade, many scaffold proteins that contain caspase‐recruitment domains (CARD) have been identified. Investigating the roles of CARD proteins has revealed that many of them play crucial roles in signaling cascades leading to activation of nuclear factor‐κB (NF‐κB). In this review, we discuss the contributions of CARD proteins to NF‐κB activation in various signaling cascades. In particular, we share some of our personal experiences during the initial investigation of the functions of the CARMA family of CARD proteins and then summarize the roles of these proteins in signaling pathways induced by antigen receptors, G protein‐coupled receptors, receptor tyrosine kinase, and C‐type lectin receptors in the context of recent progress in these field.

The CBM Complex Underwrites NF-κB Activation to Promote HER2-Associated Tumor Malignancy

“…The PKC-CBM axis also mediates EGFR-induced NF-kB activation, as we have previously shown (18). Thus, our study reveals a shared mechanism by which the CBM complex mediates NF-kB activation in response to activation of the receptors in the EGFR family, and possibly activation of other types of tyrosine kinase receptors such as fibroblast growth factor receptor, which also activates PKC (14). Further investigation is needed to determine whether the CBM complex mediates NF-kB activation when other types of tyrosine kinase receptors are activated.…”

“…The CBM complex recruits E3 ligases such as TRAF6 to activate IKK complex via ubiquitination in response to TCR stimulation (13). Similarly, CARMA3 is mainly expressed in the nonhematopoietic cells and is required for protein kinase C (PKC)-induced NF-kB activation, in which CARMA3 forms the CBM complex through a similar mechanism as that of CARMA1 (14)(15)(16). In our previous studies, we found that the CBM complex is required for G protein-coupled receptor (GPCR)-and EGFR-induced NF-kB activation (17,18).…”

Association between atopic dermatitis-related single nucleotide polymorphisms rs4722404 and psoriasis vulgaris in a southern Chinese cohort

“…The NF-kB family of transcription factors plays a crucial role in cell activation, survival, and proliferation. Aberrant NF-kB activity results in cancer, immunodeficiency, or autoimmune disorders (such as psoriasis) (Lippens et al, 2011;Jiang and Lin, 2012). Recent studies have reported an association between common SNPs and several rare mutations in the CARD14 and psoriasis (Fuchs-Telem et al, 2012;Jordan et al, 2012a,b).…”

Novel CARD11 Mutations in Human Cutaneous Squamous Cell Carcinoma Lead to Aberrant NF-κB Regulation

“…24e26 Caspase recruitment domain (CARD)-containing proteins are conserved across many species and are characterized by the presence of different functional domains shared between family members. 27 Structurally, CARD10, CARD11, and CARD14 (also known as CARMA3, CARMA1, and CARMA2) contain a CARD and a coiled-coil domain located at their aminoterminus, followed by a PDZ domain, then a SRC homology 3 (SH3) domain and a guanylate kinase-like (GUK) domain, which together constitute the membrane-associated GUK region at the carboxy-terminus. After phosphorylation, CARD proteins undergo conformational change that enables association with the downstream signaling components B-cell lymphoma protein 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1).…”

“…Formation of the complex CARD/BCL10/MALT1 is believed to be an essential step for triggering the subsequent events that lead to activation of NF-kB. 27 CARD11 is essential for antigen receptoremediated NF-kB activation in lymphocytes, 28 and mutations in the CARD and coiled-coil domains are prevalent in diffuse large B-cell lymphoma (DLBCL), leading to hyperactive NF-kB signaling and increased cell survival. 29e32 In this study, we present data supporting a tumorigenic role for CARD11 in human epidermis.…”