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
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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