Protein tyrosine phosphatase SHP2/PTPN11 mistargeting as a consequence of SH2-domain point mutations associated with Noonan Syndrome and leukemia

Pia J Müller, Kristoffer T G Rigbolt, Dirk Paterok, Jacob Piehler, Jens Vanselow, Edwin Lasonder, Jens S. Andersen, Fred Schaper, Radoslaw M Sobota

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

SHP2/PTPN11 is a key regulator of cytokine, growth factor and integrin signaling. SHP2 influences cell survival, proliferation and differentiation by regulating major signaling pathways. Mutations in PTPN11 cause severe diseases like Noonan, LEOPARD syndrome or leukemia. Whereas several of these mutations result in altered enzymatic activity due to impaired auto-inhibition, not all disease patterns can be explained by this mechanism. In this study we analyzed altered binding properties of disease-related SHP2-mutants bearing point mutations within the SH2-domain (T42A, E139D, and R138Q). Mutants were chosen according to SPR assays, which revealed different binding properties of mutated SH2 towards phosphorylated receptor peptides. To analyze global changes in mutant binding properties we applied quantitative mass spectrometry (SILAC). Using an in vitro approach we identified overall more than 1000 protein candidates, which specifically bind to the SH2-domain of SHP2. We discovered that mutations in the SH2-domain selectively affected protein enrichment by altering the binding capacity of the SH2-domain. Mutation-dependent, enhanced or reduced exposure of SHP2 to its binding partners could have an impact on the dynamics of signaling networks. Thus, disease-associated mutants of SHP2 should not only be discussed in the context of deregulated auto-inhibition but also with respect to deregulated protein targeting of the SHP2 mutants.
Original languageEnglish
JournalJournal of Proteomics
Volume84
Issue number12
Pages (from-to)132-47
ISSN1874-3919
DOIs
Publication statusPublished - 2013

Keywords

  • Amino Acid Substitution
  • HeLa Cells
  • Humans
  • Leukemia
  • Mutation, Missense
  • Neoplasm Proteins
  • Noonan Syndrome
  • Protein Binding
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • src Homology Domains

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