Defining the combinatorial space of PKC::CARD‐CC signal transduction nodes
Autor: | Mira Haegman, Marja Kreike, Harald Braun, Rudi Beyaert, Inna S. Afonina, Marie Lork, Jens Staal, Yasmine Driege, Domien Vanneste, Styliani Iliaki |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
CARD11 Transfection Biochemistry 03 medical and health sciences 0302 clinical medicine Animals Humans Protein Isoforms Protein Interaction Domains and Motifs Amino Acid Sequence Phosphorylation Molecular Biology Phylogeny Protein Kinase C Protein kinase C Binding Sites Sequence Homology Amino Acid biology Chemistry HEK 293 cells PKCS Intracellular Signaling Peptides and Proteins NF-kappa B Cell Biology Paracaspase B-Cell CLL-Lymphoma 10 Protein Recombinant Proteins Ubiquitin ligase Cell biology CARD Signaling Adaptor Proteins HEK293 Cells 030104 developmental biology Gene Expression Regulation Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein 030220 oncology & carcinogenesis biology.protein Signal transduction Sequence Alignment Plasmids Protein Binding Signal Transduction |
Zdroj: | The FEBS Journal. 288:1630-1647 |
ISSN: | 1742-4658 1742-464X |
Popis: | Signal transduction typically displays a so-called bow-tie topology: Multiple receptors lead to multiple cellular responses but the signals all pass through a narrow waist of central signaling nodes. One such signaling node for several inflammatory and oncogenic signaling pathways is the CARD-CC/BCL10/MALT1 (CBM) complexes, which get activated by protein kinase C (PKC)-mediated phosphorylation of the caspase activation and recruitment domain (CARD)-coiled-coil domain (CC) component. In humans, there are four CARD-CC family proteins (CARD9, CARD10, CARD11, and CARD14) and 9 true PKC isozymes (α to ι). At this moment, less than a handful of PKC::CARD-CC relationships are known. In order to explore the biologically relevant combinatorial space out of all 36 potential permutations in this two-component signaling event, we made use of CARD10-deficient human embryonic kidney 293T cells for subsequent pairwise cotransfections of all CARD-CC family members and all activated PKCs. Upon analysis of NF-κB-dependent reporter gene expression, we could define specific PKC::CARD-CC relationships. Surprisingly, as many as 21 PKC::CARD-CC functional combinations were identified. CARD10 was responsive to most PKCs, while CARD14 was mainly activated by PKCδ. The CARD11 activation profile was most similar to that of CARD9. We also discovered the existence of mixed protein complexes between different CARD-CC proteins, which was shown to influence their PKC response profile. Finally, multiple PKCs were found to use a common phosphorylation site to activate CARD9, while additional phosphorylation sites contribute to CARD14 activation. Together, these data reveal the combinatorial space of PKC::CARD-CC signal transduction nodes, which will be valuable for future studies on the regulation of CBM signaling. |
Databáze: | OpenAIRE |
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