Tyrosine phosphatase activity is restricted by basic charge substituting mutation of substrates

Phosphorylation controls important cellular signals and its dysregulation leads to disease. While most phospho-regulation studies are focused on kinases, phosphatases are comparatively overlooked. Combining peptide arrays with SAMDI mass spectrometry, we show that tyrosine phosphatase activity is restricted by basic amino acids adjacent to phosphotyrosines. We validate this model using two beta-catenin mutants associated with cancer (T653R/K) and a mouse model for intellectual disability (T653K). These mutants introduce a basic residue next to Y654, an established phosphorylation site where modification shifts beta-catenin from cell-cell adhesions and towards its essential nuclear role as Wnt-signaling effector. We show that T653-basic mutant beta-catenins are less efficiently dephosphorylated by phosphatases, leading to sustained Y654 phosphorylation and elevated Wnt signals, similar to those observed for Y654E phospho-mimic mutant mice. This model rationalizes how basic mutations proximal to phosphotyrosines can restrict counter-regulation by phosphatases, providing new mechanismistic and treatment insights for 6000+ potentially relevant cancer mutations.

Automated summary

Phosphorylation plays a crucial role in cellular signaling, and dysregulation of phosphorylation can lead to diseases. However, while most studies focus on kinases, the role of phosphatases is often overlooked. This study demonstrates that basic amino acids adjacent to phosphotyrosines can restrict the activity of tyrosine phosphatases, providing insights into the mechanisms underlying disease-associated mutations and potential treatment strategies.