Modelling cellular signal communication mediated by phosphorylation dependent interaction with 14-3-3 proteins

Abstract

The 14-3-3 proteins are important effectors of Ser/Thr phosphorylation in eukaryotic cells. Using mathematical modelling we investigated the roles of these proteins as effectors in signalling pathways that involve multi-phosphorylation events. We defined optimal conditions for positive and negative cross-talk. Particularly, synergistic signal interaction was evident at very different sets of binding affinities and phosphorylation kinetics. We identified three classes of 14-3-3 targets that all have two binding sites, but displayed synergistic interaction between converging signalling pathways for different ranges of parameter values. Consequently, these protein targets will respond differently to interventions that affect 14-3-3 binding affinities or phosphorylation kinetics.

Keywords: 14-3-3; AANAT; Bad; Bcl-2 antagonist of cell death; Cdc25B; Cross-talk; Foxo4; MAPKAP-K1; Modelling; PAK1; RGS18; Raf proto-oncogene ser/thr protein kinase; Rap1 GTPase activating protein 2; Rap1GAP2; S1; S2; Signalling; Synergy; TP; TP phosphorylated on site n; aralkylamine N-acetyltransferase; c-Raf/Raf-1; cell division cycle 25B; cyclin-dependent kinase inhibitor 1B/p27; forkhead box protein O4; mitogen activated protein kinase activated protein kinase 1; p21 protein (Cdc42/Rac)-activated kinase 1; p27Kip1; pSn-TP; phosphorylation rate constant ratio site n; r(S); r(n); regulator of G-protein signalling 18; signal 1; signal 2; synergy ratio; target protein.