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

Che Fan Huang, Cara J. Gottardi*, Milan Mrksich*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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 β-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 β-catenin from cell–cell adhesions and towards its essential nuclear role as Wnt-signaling effector. We show that T653-basic mutant β-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.

Original languageEnglish (US)
Article number15095
JournalScientific reports
Volume12
Issue number1
DOIs
StatePublished - Dec 2022

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'Tyrosine phosphatase activity is restricted by basic charge substituting mutation of substrates'. Together they form a unique fingerprint.

Cite this