Generation and functional characterization of a BCL10-inhibitory peptide that represses NF-κB activation

Marasco, Daniela; Stilo, Romania; Sandomenico, Annamaria; Monti, Simona Maria; Tizzano, Barbara; Capua, Antonia De; Varricchio, Ettore; Liguoro, Domenico; Zotti, Tiziana; Formisano, Silvestro; Ruvo, Menotti; Vito, Pasquale

doi:10.1042/bj20090055

Cited by 11 publications

(9 citation statements)

References 40 publications

(45 reference statements)

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“…However, they exhibit distinct expression profiles; CARMA1 is expressed in hematopoietic cells, CARMA2 in the placenta, and CARMA3 in all non-hematopoietic cells [1]–[4]. Recent studies have demonstrated that CARMA3, as a scaffold protein, plays a critical role in GPCR ligands and PKC-induced NF-κB activation [5]–[8]. It has been previously demonstrated that NF-κB activation is involved in tumorigenesis and in the development of neural, heart, and immune diseases [9]–[13].…”

Section: Introductionmentioning

confidence: 99%

Overexpression of CARMA3 in Non-Small-Cell Lung Cancer Is Linked for Tumor Progression

Dong

et al. 2012

PLoS ONE

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We aimed to investigate the clinical significance of the expression of novel scaffold protein CARMA3 in non-small-cell lung cancer (NSCLC) and the biological function of CARMA3 in NSCLC cell lines. We observed moderate to high CARMA3 staining in 68.8% of 141 NSCLC specimens compared to corresponding normal tissues. The overexpression of CARMA3 was significantly correlated with TNM stage (P = 0.022) and tumor status (P = 0.013). CARMA3 upregulation also correlated with a shorter survival rate of patients of nodal status N0 (P = 0.042)as well as the expression of epidermal growth factor receptor (EGFR) (P = 0.009). In EGFR mutation positive cases, CARMA3 expression was much higher (87.5%) compared to non-mutation cases (66.1%). In addition, we observed that knockdown of CARMA3 inhibits tumor cell proliferation and invasion, and induces cell cycle arrest at the boundary between the G1 and S phase. We further demonstrated a direct link between CARMA3 and NF-κB activation. The change of biological behavior in CARMA3 knockdown cells may be NF-κB-related. Our findings demonstrated, for the first time, that CARMA3 was overexpressed in NSCLC and correlated with lung cancer progression, EGFR expression, and EGFR mutation. CARMA3 could serve as a potential companion drug target, along with NF-kB and EGFR in EGFR-mutant lung cancers.

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Section: Introductionmentioning

confidence: 99%

Overexpression of CARMA3 in Non-Small-Cell Lung Cancer Is Linked for Tumor Progression

Dong

et al. 2012

PLoS ONE

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“…Thus, we tested whether liposome-assisted delivery of a BCL10 inhibitory peptide 30 could reduce NF- κ B activation in NHEK exposed to PAMPs. Indeed, the expression level of two monitored NF- κ B target genes was partially but significantly diminished when NHEK were treated with a BCL10 inhibitory peptide, but not a control peptide (Figure 6).…”

Section: Resultsmentioning

confidence: 99%

CARMA2sh and ULK2 control pathogen-associated molecular patterns recognition in human keratinocytes: psoriasis-linked CARMA2sh mutants escape ULK2 censorship

et al. 2017

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The molecular complexes formed by specific members of the family of CARMA proteins, the CARD domain-containing adapter molecule BCL10 and MALT1 (CBM complex) represent a central hub in regulating activation of the pleiotropic transcription factor NF-κB. Recently, missense mutations in CARMA2sh have been shown to cause psoriasis in a dominant manner and with high penetrancy. Here, we demonstrate that in human keratinocytes CARMA2sh plays an essential role in the signal transduction pathway that connects pathogen-associated molecular patterns recognition to NF-κB activation. We also find that the serine/threonine kinase ULK2 binds to and phosphorylates CARMA2sh, thereby inhibiting its capacity to activate NF-κB by promoting lysosomal degradation of BCL10, which is essential for CARMA2sh-mediated NF-κB signaling. Remarkably, CARMA2sh mutants associated with psoriasis escape ULK2 inhibition. Finally, we show that a peptide blocking CARD-mediated BCL10 interactions reduces the capacity of psoriasis-linked CARMA2sh mutants to activate NF-κB. Our work elucidates a fundamental signaling mechanism operating in human keratinocytes and opens to novel potential tools for the therapeutical treatment of human skin disorders.

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“…This is even more important in the light of attempts to devise molecular tools capable of modulating the activation of this transcription factor, and certainly attempts to devise molecular tools capable of modulating the activation of this transcription factor will benefit of this information [26] .…”

Section: Discussionmentioning

confidence: 99%

The Dishevelled, EGL-10 and Pleckstrin (DEP) Domain-Containing Protein DEPDC7 Binds to CARMA2 and CARMA3 Proteins, and Regulates NF-κB Activation

et al. 2014

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The molecular complexes containing BCL10, MALT1 and CARMA proteins (CBM complex) have been recently identified as a key component in the signal transduction pathways that regulate activation of Nuclear Factor kappaB (NF-κB) transcription factor. Herein we identified the DEP domain-containing protein DEPDC7 as cellular binding partners of CARMA2 and CARMA3 proteins. DEPDC7 displays a cytosolic distribution and its expression induces NF-κB activation. Conversely, shRNA-mediated abrogation of DEPDC7 results in impaired NF-κB activation following G protein-coupled receptors stimulation, or stimuli that require CARMA2 and CARMA3, but not CARMA1. Thus, this study identifies DEPDC7 as a CARMA interacting molecule, and provides evidence that DEPDC7 may be required to specifically convey on the CBM complex signals coming from activated G protein-coupled receptors.

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Generation and functional characterization of a BCL10-inhibitory peptide that represses NF-κB activation

Cited by 11 publications

References 40 publications

Overexpression of CARMA3 in Non-Small-Cell Lung Cancer Is Linked for Tumor Progression

Overexpression of CARMA3 in Non-Small-Cell Lung Cancer Is Linked for Tumor Progression

CARMA2sh and ULK2 control pathogen-associated molecular patterns recognition in human keratinocytes: psoriasis-linked CARMA2sh mutants escape ULK2 censorship

The Dishevelled, EGL-10 and Pleckstrin (DEP) Domain-Containing Protein DEPDC7 Binds to CARMA2 and CARMA3 Proteins, and Regulates NF-κB Activation

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