Cell signaling regulation by protein phosphorylation: a multivariate, heterogeneous, and context-dependent process

Evan K Day, Nisha G Sosale, Matthew J Lazzara
2016 Current Opinion in Biotechnology  
Proper spatiotemporal regulation of protein phosphorylation in cells and tissues is required for normal development and homeostasis, but aberrant protein phosphorylation regulation leads to various diseases. The study of signaling regulation by protein phosphorylation is complicated in part by the sheer scope of the kinome and phosphoproteome, dependence of signaling protein functionality on cellular localization, and the complex multivariate relationships that exist between protein
more » ... ion dynamics and the cellular phenotypes they control. Additional complexities arise from the ability of microenvironmental factors to influence phosphorylationdependent signaling and from the tendency for some signaling processes to occur heterogeneously among cells. These considerations should be taken into account when measuring cell signaling regulation by protein phosphorylation. Cell signaling regulation by protein phosphorylation Cell signaling is the biochemical process by which cells are cued to respond to perturbations in their environment. In one example, ligand binding to the extracellular domain of a receptor initiates a network of intracellular biochemical reactions that affect cell phenotypes by modifying gene expression, metabolism, or cytoskeletal arrangements. Signaling regulates most normal cell processes, but improper signaling results in numerous diseases. Many biomolecules participate in signaling, including proteins, amino acids, lipids, and second messengers (e.g., cyclic AMP, inositol triphosphate). The focus here is signaling regulation by protein phosphorylation, which plays several mechanistic roles. Phosphorylation generally receives greater attention than other post-translational modifications, in part because kinases are often over-expressed or mutated in disease, especially cancer. As a result, many inhibitors and antibodies have been developed to antagonize the activity of kinases. Protein phosphorylation by kinases: Mechanistic aspects and signaling regulatory roles Protein phosphorylation is a reversible process wherein phosphate from ATP (or other nucleoside phosphates) is esterified to amino acids by protein kinases. Serine and threonine phosphorylation are the most common phosphorylation events, with tyrosine accounting for <1% of the total esterified phosphate. Other amino acids, including histidine and lysine, can be phosphorylated, but roles of these events have not been deeply investigated. In humans, 518 protein kinases control phosphorylation. 90 are tyrosine kinases, and 56 are transmembrane receptors (receptor tyrosine kinases, RTK). The remaining 372 are serine/threonine kinases, some of which are receptors, and dual specificity protein kinases (tyrosine and serine/threonine). Protein kinases have conserved structural motifs including an activation loop, catalytic domain, and ATP binding domain. Many kinase structures have been solved, which has aided inhibitor design.
doi:10.1016/j.copbio.2016.06.005 pmid:27393828 pmcid:PMC4975652 fatcat:xoxs7enrxraizbekanko6oqxdq