Format

Send to

Choose Destination
Mol Cell Biol. 2013 Jan;33(2):429-43. doi: 10.1128/MCB.00850-12. Epub 2012 Nov 12.

A quantitative signaling screen identifies CARD11 mutations in the CARD and LATCH domains that induce Bcl10 ubiquitination and human lymphoma cell survival.

Author information

1
Department of Biological Chemistry and Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Abstract

Antigen receptor signaling to NF-κB, essential for normal lymphocyte activation, is dysregulated in several types of lymphoma. During normal signaling, the multidomain adapter CARD11 transitions from a closed, inactive state to an open, active scaffold that assembles a multiprotein complex, leading to NF-κB activation. The regulation of CARD11 scaffold function is bypassed by lymphoma-associated oncogenic CARD11 mutations that induce spontaneous signaling. We report an unbiased high-throughput quantitative signaling screen that identifies new CARD11 hyperactive variants and defines a LATCH domain that functions with the CARD to promote CARD11 autoinhibition. Gain-of-function mutations in the LATCH or CARD disrupt inhibitory domain binding, promote Bcl10 association, and induce Bcl10 ubiquitination, NF-κB activation, and human lymphoma cell survival. Our results identify CARD11 mutations with oncogenic potential, provide a mechanistic explanation for their signaling potency, and offer a straightforward method for the discovery of variants that promote the tumorigenesis of NF-κB-dependent lymphomas.

PMID:
23149938
PMCID:
PMC3554118
DOI:
10.1128/MCB.00850-12
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center