Crosstalk between phosphorylation and O‐GlcNAcylation: friend or foe

A wide variety of protein post‐translational modifications (PTMs) decorate cellular proteins, regulating their structure, interactions and ultimately their function. The density of co‐occurring PTMs on proteins can be very high, where multiple PTMs can positively or negatively influence each other's actions, termed PTM crosstalk. In this review, we highlight recent progress in the area of PTM crosstalk, whereby we focus on crosstalk between protein phosphorylation and O‐GlcNAcylation. These two PTMs largely target identical (i.e., Ser and Thr) amino acids in proteins. Phosphorylation/O‐GlcNAcylation crosstalk comes in many flavors, for instance by competition for the same site/residue (reciprocal crosstalk), as well as by modifications influencing each other in proximity or even distal on the protein sequence. PTM crosstalk is observed on the writers of these modifications (i.e., kinases and O‐GlcNAc transferase), on the erasers (i.e., phosphatases and O‐GlcNAcase), and on the readers and the substrates. We describe examples of all these different flavors of crosstalk, and additionally the methods that are emerging to better investigate in particular phosphorylation/O‐GlcNAcylation crosstalk. Proteins can be modified by multiple, different post‐translational modifications (PTMs), which act to regulate protein structure and function. When the presence of one PTM affects another, this is termed PTM crosstalk. In this review, we highlight recent progress in the area of PTM crosstalk, focusing in particular on the crosstalk that exists between protein phosphorylation and an intracellular form of glycosylation, termed O‐GlcNAcylation.