Isolation of a distinct class of gain-of-function SHP-2 mutants with oncogenic RAS-like transforming activity from solid tumors.
SHP-2 protein tyrosine phosphatase plays an important role in activation of the RAS-dependent signaling. Gain-of-function mutations in the PTPN11 gene, which encodes SHP-2, have been found in the leukemia-prone developmental disorder Noonan syndrome as well as sporadic childhood leukemias, indicating that SHP-2 is a bona fide human oncoprotein. However, the role of SHP-2 mutations in non-hematological malignancies remains obscure. Here, we screened for PTPN11 mutations in primary solid tumors and identified a 1520C>A mutation that causes threonine-507 to lysine (T507K) substitution in the phosphatase domain of SHP-2 in a case of hepatocellular carcinoma. T507K SHP-2 exhibited altered substrate specificity with slightly elevated basal phosphatase activity. Upon expression in NIH3T3 cells, T507K SHP-2 induced transformed foci, which was not observed with wild type, Noonan-specific or leukemia-specific SHP-2. Furthermore, NIH3T3 cells transformed by T507K SHP-2 showed anchorage-independent growth and developed tumors in nude mice. These results indicate that quantitative and/or qualitative alteration in phosphatase activity determines the transforming potential as well as target cell/tissue spectrum of individual SHP-2 mutants as oncoproteins. Although rare in solid tumors, the identified T507K SHP-2 represents a distinct class of SHP-2 mutants with oncogenic RAS-like transforming activity, which could contribute to the development of solid tumors.
Miyamoto
D
D
Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
Miyamoto
M
M
Takahashi
A
A
Yomogita
Y
Y
Higashi
H
H
Kondo
S
S
Hatakeyama
M
M
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009154:Mutation; D041681:NIH 3T3 Cells; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics* / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse; D018631:ras Proteins