Abstract
The CARMA–Bcl10–MALT1 (CBM) signalosome is an intracellular protein complex composed of a CARMA scaffolding protein, the Bcl10 linker protein, and the MALT1 protease. This complex was first recognized because the genes encoding its components are targeted by mutation and chromosomal translocation in lymphoid malignancy. We now know that the CBM signalosome plays a critical role in normal lymphocyte function by mediating antigen receptor-dependent activation of the pro-inflammatory, pro-survival NF-κB transcription factor, and that deregulation of this signaling complex promotes B-cell lymphomagenesis. More recently, we and others have demonstrated that a CBM signalosome also operates in cells outside of the immune system, including in several solid tumors. While CARMA1 (also referred to as CARD11) is expressed primarily within lymphoid tissues, the related scaffolding protein, CARMA3 (CARD10), is more widely expressed and participates in a CARMA3-containing CBM complex in a variety of cell types. The CARMA3-containing CBM complex operates downstream of specific G protein-coupled receptors (GPCRs) and/or growth factor receptor tyrosine kinases (RTKs). Since inappropriate expression and activation of GPCRs and/or RTKs underlies the pathogenesis of several solid tumors, there is now great interest in elucidating the contribution of CARMA3-mediated cellular signaling in these malignancies. Here, we summarize the key discoveries leading to our current understanding of the role of CARMA3 in solid tumor biology and highlight the current gaps in our knowledge.
Highlights
In the late 1990s, a large family of proteins containing a homophilic protein–protein interaction module referred to as a “caspase activation and recruitment domain” (CARD) was discovered [1]
In 2000, CARD9 was identified as a protein that directly interacts with the CARD of Bcl10, a signaling protein involved in regulating NF-κB [2]
We found that the CARMA3-containing CBM complex can promote NF-κB activation in cells outside of the immune system
Summary
In the late 1990s, a large family of proteins containing a homophilic protein–protein interaction module referred to as a “caspase activation and recruitment domain” (CARD) was discovered [1]. We found that the CARMA3-containing CBM complex (abbreviated as C3BM) can promote NF-κB activation in cells outside of the immune system These initial studies all demonstrated that the C3BM complex operates downstream of specific GPCRs that are known to stimulate PKC (Figure 1C) [43,44,45]. The discovery that the C3BM complex functions downstream of GPCRs to activate the pro-oncogenic NF-κB transcription factor in non-immune cells raised the possibility that the CARMA3-containing CBM complex might play a role in solid tumor pathogenesis. A subsequent study demonstrated that the C3BM complex plays an important role in the pathophysiology of LPAinduced ovarian cancer cell migration and invasion (Table 1A) [51] These authors showed that siRNA-mediated knockdown of either CARMA3, Bcl, or MALT1 suppressed LPA-induced NF-κB activation in ovarian cancer cell models. Breast cancer Oral squamous cell carcinoma Ovarian cancer (B) GPCRs in non-malignant cells
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