Caspase recruitment domain-containing protein 11 also known as CARD-containing MAGUK protein 1 (Carma 1) is a protein in the CARD-CC protein family that in humans is encoded by the CARD11 gene. CARD 11 is a membrane associated protein that is found in various human tissues, including the thymus, spleen, liver, and peripheral blood leukocytes. Similarly, CARD 11 is also found in abundance in various lines of cancer cells.
Function
The protein encoded by this gene belongs to the membrane-associated guanylate kinase (MAGUK) family, a class of proteins that functions as molecular scaffolds for the assembly of multiprotein complexes at specialized regions of the plasma membrane. This protein is also a member of the CARD protein family, which is defined by carrying a characteristic caspase-associated recruitment domain (CARD). CARD11 (CARMA1) has a domain structure similar to that of CARD10 (CARMA3) and CARD14 (CARMA2) as a member of the CARD-CC family with a C terminal MAGUK domain (the so-called CARMA proteins). The CARD domain of proteins in the CARD-CC family have been shown to specifically interact with BCL10, a protein known to function as a positive regulator of NF-κB activation by recruitment and activation of MALT1. When overexpressed in cells, this protein family activates NF-κB and induces the phosphorylation of BCL10.
CARD11 is critical for T cell and B cell function and is activated after T cell receptor or B cell receptor stimulation. After receptor stimulation, CARD11 is phosphorylated by PKC-θ (in T cells) or PKC-β (in B cells). The phosphorylation induces formation of filamentous CARD11 multimers that recruit BCL10 and MALT1, which in turn activates NF-κB. Loss of function mutations in CARD11 cause severe combined immunodeficiency (SCID) since the function of cells critical for adaptive immunity are disrupted.
Structure
The structure of CARD11 involves multiple domains that impact the protein's ability to activate BCL10 and NF-κB activity. CARD11 has a CARD domain, a serine-threonine rich region, is associated with the N-terminus, which is essential for NF-κB signaling activity. The region following the CARD domain is highly coiled. In deleting the CARD domain, all NF-κB signaling activity was prevented. The CARD domain on CARD11 interacts with the CARD domain on BCL10 to initiate the signaling pathway.
On the C-terminus of CARD11 there is the MAGUK domain that is associated with the cell membrane. This domain is often referred to as to as the inhibitory domain. Protein kinase C activates CARD11 by phosphorylating serine residues within the inhibitory domain.
Interactions
CARD11 has been shown to interact with BCL10. This interaction occurs between the CARD domain on BCL10 and the CARD domain on CARD11, and results in signal propagation and NF-κB activation.
External links
- Human CARD11 genome location and CARD11 gene details page in the UCSC Genome Browser.
Further reading
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- Sanger Centre, The; Washington University Genome Sequencing Cente, The (1998). "Toward a complete human genome sequence". Genome Res. 8 (11): 1097–108. doi:10.1101/gr.8.11.1097. PMID 9847074.
- Wang L, Guo Y, Huang WJ, Ke X, Poyet JL, Manji GA, Merriam S, Glucksmann MA, DiStefano PS, Alnemri ES, Bertin J (2001). "Card10 is a novel caspase recruitment domain/membrane-associated guanylate kinase family member that interacts with BCL10 and activates NF-kappa B". J. Biol. Chem. 276 (24): 21405–9. doi:10.1074/jbc.M102488200. PMID 11259443.
- Wang D, You Y, Case SM, McAllister-Lucas LM, Wang L, DiStefano PS, Nuñez G, Bertin J, Lin X (2002). "A requirement for CARMA1 in TCR-induced NF-kappa B activation". Nat. Immunol. 3 (9): 830–5. doi:10.1038/ni824. PMID 12154356. S2CID 19250072.
- Gaide O, Favier B, Legler DF, Bonnet D, Brissoni B, Valitutti S, Bron C, Tschopp J, Thome M (2002). "CARMA1 is a critical lipid raft-associated regulator of TCR-induced NF-kappa B activation". Nat. Immunol. 3 (9): 836–43. doi:10.1038/ni830. PMID 12154360. S2CID 42949809.
- Pomerantz JL, Denny EM, Baltimore D (2002). "CARD11 mediates factor-specific activation of NF-kappaB by the T cell receptor complex". EMBO J. 21 (19): 5184–94. doi:10.1093/emboj/cdf505. PMC 129028. PMID 12356734.
- Wang D, Matsumoto R, You Y, Che T, Lin XY, Gaffen SL, Lin X (2004). "CD3/CD28 costimulation-induced NF-kappaB activation is mediated by recruitment of protein kinase C-theta, Bcl10, and IkappaB kinase beta to the immunological synapse through CARMA1". Mol. Cell. Biol. 24 (1): 164–71. doi:10.1128/MCB.24.1.164-171.2003. PMC 303359. PMID 14673152.
- Stilo R, Liguoro D, Di Jeso B, Formisano S, Consiglio E, Leonardi A, Vito P (2004). "Physical and functional interaction of CARMA1 and CARMA3 with Ikappa kinase gamma-NFkappaB essential modulator". J. Biol. Chem. 279 (33): 34323–31. doi:10.1074/jbc.M402244200. PMID 15184390.
- Lee KY, D'Acquisto F, Hayden MS, Shim JH, Ghosh S (2005). "PDK1 nucleates T cell receptor-induced signaling complex for NF-kappaB activation". Science. 308 (5718): 114–8. Bibcode:2005Sci...308..114L. doi:10.1126/science.1107107. PMID 15802604. S2CID 84389997.
- Shinohara H, Yasuda T, Aiba Y, Sanjo H, Hamadate M, Watarai H, Sakurai H, Kurosaki T (2005). "PKC beta regulates BCR-mediated IKK activation by facilitating the interaction between TAK1 and CARMA1". J. Exp. Med. 202 (10): 1423–31. doi:10.1084/jem.20051591. PMC 2212994. PMID 16301747.
- Sommer K, Guo B, Pomerantz JL, Bandaranayake AD, Moreno-García ME, Ovechkina YL, Rawlings DJ (2005). "Phosphorylation of the CARMA1 linker controls NF-kappaB activation". Immunity. 23 (6): 561–74. doi:10.1016/j.immuni.2005.09.014. PMID 16356855.
- Matsumoto R, Wang D, Blonska M, Li H, Kobayashi M, Pappu B, Chen Y, Wang D, Lin X (2005). "Phosphorylation of CARMA1 plays a critical role in T Cell receptor-mediated NF-kappaB activation". Immunity. 23 (6): 575–85. doi:10.1016/j.immuni.2005.10.007. PMID 16356856.
- Narayan P, Holt B, Tosti R, Kane LP (2006). "CARMA1 is required for Akt-mediated NF-kappaB activation in T cells". Mol. Cell. Biol. 26 (6): 2327–36. doi:10.1128/MCB.26.6.2327-2336.2006. PMC 1430296. PMID 16508008.
- Ishiguro K, Avruch J, Landry A, Qin S, Ando T, Goto H, Xavier R (2006). "Nore1B regulates TCR signaling via Ras and Carma1". Cell. Signal. 18 (10): 1647–54. doi:10.1016/j.cellsig.2006.01.015. PMC 3204664. PMID 16520020.
- Ishiguro K, Green T, Rapley J, Wachtel H, Giallourakis C, Landry A, Cao Z, Lu N, Takafumi A, Goto H, Daly MJ, Xavier RJ (2006). "Ca2+/calmodulin-dependent protein kinase II is a modulator of CARMA1-mediated NF-kappaB activation". Mol. Cell. Biol. 26 (14): 5497–508. doi:10.1128/MCB.02469-05. PMC 1592706. PMID 16809782.