Abstract
The SH2 domain-containing protein-tyrosine phosphatase PTPN11 (Shp2) is required for normal development and is an essential component of signaling pathways initiated by growth factors, cytokines, and extracellular matrix. In many of these pathways, Shp2 acts upstream of Ras. About 50% of patients with Noonan syndrome have germ-line PTPN11 gain of function mutations. Associations between Noonan syndrome and an increased risk of some malignancies, notably leukemia and neuroblastoma, have been reported, and recent data indicate that somatic PTPN11 mutations occur in children with sporadic juvenile myelomonocytic leukemia, myelodysplasic syndrome, B-cell acute lymphoblastic leukemia, and acute myelogenous leukemia (AML). Juvenile myelomonocytic leukemia patients without PTPN11 mutations have either homozygotic NF-1 deletion or activating RAS mutations. Given the role of Shp2 in Ras activation and the frequent mutation of RAS in human tumors, these data raise the possibility that PTPN11 mutations play a broader role in cancer. We asked whether PTPN11 mutations occur in other malignancies in which activating RAS mutations occur at low but significant frequency. Sequencing of PTPN11 from 13 different human neoplasms including breast, lung, gastric, and neuroblastoma tumors and adult AML and acute lymphoblastic leukemia revealed 11 missense mutations. Five are known mutations predicted to result in an activated form of Shp2, whereas six are new mutations. Biochemical analysis confirmed that several of the new mutations result in increased Shp2 activity. Our data demonstrate that mutations in PTPN11 occur at low frequency in several human cancers, especially neuroblastoma and AML, and suggest that Shp2 may be a novel target for antineoplastic therapy.
Highlights
Protein-tyrosine phosphatases (PTPs) have key positive (signalenhancing) or negative (signal-attenuating) roles in a variety of nor-[1, 7]
Protein-tyrosine phosphatases (PTPs) have key positive or negative roles in a variety of nor-(1, 7)
DNA samples from prostate cancers were obtained from the Department of Medical Oncology at the Dana-Farber Cancer Institute (Boston, MA); acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and polycythemia vera (PV) DNAs were provided by the Department of Medicine at the Brigham and Women’s Hospital, and melanoma DNAs were from the Department of Pediatric Hematology/Oncology at the Dana-Farber Cancer Institute and Children’s Hospital (Boston, MA)
Summary
Protein-tyrosine phosphatases (PTPs) have key positive (signalenhancing) or negative (signal-attenuating) roles in a variety of nor-[1, 7]. Most PTPN11 mutations in NS and leukemia affect N-SH2 or PTP domain residues involved in basal inhibition of Shp2 [4]. DNA samples from human colon tumors were described previously [11].
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