title: A quantitative signaling screen identifies CARD11 mutations in the CARD and LATCH domains that induce Bcl10 ubiquitination and human lymphoma cell survival.
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.
authors.affiliation: Department of Biological Chemistry and Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Waipan
authors.initials: W
authors.lastname: Chan
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Schaffer
authors.forename: Joel L
authors.initials: JL
authors.lastname: Pomerantz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics* / Q000378:metabolism; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival; D005069:Evaluation Studies as Topic; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D006162:Guanylate Cyclase / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D047468:Immunoprecipitation; D008213:Lymphocyte Activation / Q000235:genetics; D008223:Lymphoma / Q000235:genetics* / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008979:Moloney murine leukemia virus / Q000235:genetics / Q000378:metabolism; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D011946:Receptors, Antigen / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D054875:Ubiquitination; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins; D020169:Caspases; D006162:Guanylate Cyclase; D051550:I-kappa B Kinase; D020930:MAP Kinase Kinase Kinases; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011946:Receptors, Antigen; D000099151:MAP Kinase Kinase Kinase 7; C118591:BCL10 protein, human; C400109:MALT1 protein, human; C426242:CARD11 protein, human