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

• Type of Material: Article
• Authors: Xia Liu, Case Western Reserve University; Hong Zheng, Case Western Reserve University; Xiaobo Li, Case Western Reserve University; Siying Wang, Case Western Reserve University; Howard J. Meyerson, Case Western Reserve University; Wentian Yang, Brown University; Benjamin G. Neel, University of Toronto; Cheng-Kui Qu, Emory University
• Language: English
• Date: 2016-01-26
• Publisher: National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: 2016 NAS
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1508535113
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences
• Volume: 113
• Issue: 4
• Start Page: 984
• End Page: 989
• Grant/Funding Information: This work was supported by National Institutes of Health Grants CA181754 and DK092722 (to C.-K.Q.).
• Keywords: ACUTE MYELOID-LEUKEMIA; Multidisciplinary Sciences; DISEASE; PROTEIN-TYROSINE-PHOSPHATASE; JUVENILE MYELOMONOCYTIC LEUKEMIA; POLO-LIKE KINASE-1; Science & Technology; ANEUPLOIDY; chromosomal instability; CHROMOSOMAL INSTABILITY; CANCER; protein tyrosine phosphatase; ACTIVATION; NOONAN-SYNDROME; mitosis; Ptpn11; Science & Technology - Other Topics; Shp2
• Research Categories: Health Sciences, Oncology

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 damageinduced 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.