title: Gain-of-function mutations of Ptpn11 (Shp2) cause aberrant mitosis and increase susceptibility to DNA damage-induced malignancies.
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.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106;
authors.forename: Xia
authors.initials: X
authors.lastname: Liu
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106; Division of Hematology/Oncology, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, GA 30322;
authors.forename: Hong
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106; Division of Hematology/Oncology, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, GA 30322;
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Li
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106;
authors.forename: Siying
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106;
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Meyerson
authors.affiliation: Department of Orthopaedics, Brown University Alpert Medical School, Providence, RI 02912;
authors.forename: Wentian
authors.initials: W
authors.lastname: Yang
authors.affiliation: Princess Margaret Cancer Center, Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Neel
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106; Division of Hematology/Oncology, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, GA 30322; cheng-kui.qu@emory.edu.
authors.forename: Cheng-Kui
authors.initials: CK
authors.lastname: Qu
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D043171:Chromosomal Instability; D004249:DNA Damage; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008938:Mitosis; D009154:Mutation; D009369:Neoplasms / Q000209:etiology* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1; C516724:PTPN11 protein, human; C516725:Ptpn11 protein, mouse
keywords: Ptpn11; Shp2; chromosomal instability; mitosis; protein tyrosine phosphatase