RT Journal Article
SR Electronic
T1 Defining the relevant combinatorial space of the PKC/CARD-CC signal transduction nodes
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 228767
DO 10.1101/228767
A1 Jens Staal
A1 Yasmine Driege
A1 Mira Haegman
A1 Marja Kreike
A1 Styliani Iliaki
A1 Domien Vanneste
A1 Inna Affonina
A1 Harald Braun
A1 Rudi Beyaert
YR 2019
UL http://biorxiv.org/content/early/2019/09/24/228767.abstract
AB Biological signal transduction typically display a so-called bow-tie or hour glass topology: Multiple receptors lead to multiple cellular responses but the signals all pass through a narrow waist of central signaling nodes. One such critical signaling node for several inflammatory and oncogenic signaling pathways in humans are the CARD-CC / Bcl10 / MALT1 (CBM) complexes, which get activated by upstream protein kinase C (PKC). In humans, there are four phylogenetically distinct CARD-CC family (CARD9, −10, −11 and −14) proteins and 9 true PKC isozymes (α to ι). At this moment, less than a handful of PKC/CARD-CC relationships are known from experimental evidence. 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 CRISPR/Cas9 genome-edited HEK293T cells to mutate CARD10 for subsequent pairwise cotransfections of all CARD-CC family members and activated mutants of all true PKCs. By quantitative reporter gene expression readout, we could define specific strong and weak PKC/CARD-CC relationships. Surprisingly as many as 21 PKC/CARD-CC combinations were found to have synergistic effects. We also discovered heterodimerization between different CARD-CC proteins, and that this can influence their PKC response profile. This information will be valuable for future studies of novel signaling pathways dependent on the CBM complex signaling nodes.Bcl10B Cell CLL/Lymphoma 10CARDCaspase activation and recruitment domainCCCoiled-coil domainMALT1Mucosa-associated lymphoid tissue lymphoma translocation protein 1PKCprotein kinase C