Gain-of-function mutations of Ptpn11 (Shp2) cause aberrant mitosis and increase susceptibility to DNA damage-induced malignancies

Proc Natl Acad Sci U S A. 2016 Jan 26;113(4):984-9. doi: 10.1073/pnas.1508535113. Epub 2016 Jan 11.

Abstract

Gain-of-function (GOF) mutations of protein tyrosine phosphatase nonreceptor type 11 Ptpn11 (Shp2), a protein tyrosine phosphatase implicated in multiple cell signaling pathways, are associated with childhood leukemias and solid tumors. The underlying mechanisms are not fully understood. Here, we report that Ptpn11 GOF mutations disturb mitosis and cytokinesis, causing chromosomal instability and greatly increased susceptibility to DNA damage-induced malignancies. We find that Shp2 is distributed to the kinetochore, centrosome, spindle midzone, and midbody, all of which are known to play critical roles in chromosome segregation and cytokinesis. Mouse embryonic fibroblasts with Ptpn11 GOF mutations show a compromised mitotic checkpoint. Centrosome amplification and aberrant mitosis with misaligned or lagging chromosomes are significantly increased in Ptpn11-mutated mouse and patient cells. Abnormal cytokinesis is also markedly increased in these cells. Further mechanistic analyses reveal that GOF mutant Shp2 hyperactivates the Polo-like kinase 1 (Plk1) kinase by enhancing c-Src kinase-mediated tyrosine phosphorylation of Plk1. This study provides novel insights into the tumorigenesis associated with Ptpn11 GOF mutations and cautions that DNA-damaging treatments in Noonan syndrome patients with germ-line Ptpn11 GOF mutations could increase the risk of therapy-induced malignancies.

Keywords: Ptpn11; Shp2; chromosomal instability; mitosis; protein tyrosine phosphatase.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Cycle Proteins / metabolism
  • Chromosomal Instability
  • DNA Damage*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mitosis*
  • Mutation
  • Neoplasms / etiology*
  • Neoplasms / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / physiology*
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism

Substances

  • Cell Cycle Proteins
  • Proto-Oncogene Proteins
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1
  • PTPN11 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Ptpn11 protein, mouse