Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia.
Noonan syndrome (NS) is characterized by short stature, characteristic facial features, and heart defects. Recently, missense mutations of PTPN11, the gene encoding protein tyrosine phosphatase (PTP) SHP-2, were identified in patients with NS. Further, somatic mutations in PTPN11 were detected in childhood leukemia. Recent studies showed that the phosphatase activities of five mutations identified in NS and juvenile myelomonocytic leukemia (JMML) were increased. However, the functional properties of the other mutations remain unidentified. In this study, in order to clarify the differences between the mutations identified in NS and leukemia, we examined the phosphatase activity of 14 mutants of SHP-2. We identified nine mutations, including a novel F71I mutation, in 16 of 41 NS patients and two mutations, including a novel G503V mutation, in three of 29 patients with leukemia. Immune complex phosphatase assays of individual mutants transfected in COS7 cells showed that ten mutants identified in NS and four mutants in leukemia showed 1.4-fold to 12.7-fold increased activation compared with wild-type SHP-2. These results suggest that the pathogenesis of NS and leukemia is associated with enhanced phosphatase activity of mutant SHP-2. A comparison of the phosphatase activity in each mutant and a review of previously reported cases showed that high phosphatase activity observed in mutations at codons 61, 71, 72, and 76 was significantly associated with leukemogenesis.
Niihori
Tetsuya
T
Department of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Sendai, 980-8574, Japan.
Aoki
Yoko
Y
Department of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Sendai, 980-8574, Japan. aokiy@mail.tains.tohoku.ac.jp.
Ohashi
Hirofumi
H
Division of Medical Genetics, Saitama Children's Medical Center, Saitama, Japan.
Kurosawa
Kenji
K
Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Japan.
Kondoh
Tatsuro
T
Department of Pediatrics, Nagasaki University of Medicine, Nagasaki, Japan.
Ishikiriyama
Satoshi
S
Division of Clinical Genetics and Cytogenetics, Shizuoka Children's Hospital, Shizuoka, Japan.
Kawame
Hiroshi
H
Division of Medical Genetics, Nagano Children's Hospital, Nagano, Japan.
Kamasaki
Hotaka
H
Department of Pediatrics, Sapporo Medical University, Sapporo, Japan.
Yamanaka
Tsutomu
T
Okazaki Women's Junior College, Okazaki, Japan.
Takada
Fumio
F
Department of Medical Genetics, Kitasato University Graduate School of Medical Sciences, Sagamihara, Japan.
Nishio
Kimio
K
Department of Pediatrics, Seirei Hamamatsu General Hospital, Hamamatsu, Japan.
Sakurai
Masahiro
M
Department of Cardiovascular Surgery, Tohoku University School of Medicine, Sendai, Japan.
Tamai
Hiroshi
H
Department of Pediatrics, Osaka Medical College, Osaka, Japan.
Nagashima
Tatsuro
T
Department of Pediatrics, Jikei University Hospital, Tokyo, Japan.
Suzuki
Yoichi
Y
Department of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Sendai, 980-8574, Japan.
Kure
Shigeo
S
Department of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Sendai, 980-8574, Japan.
Fujii
Kunihiro
K
Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan.
Imaizumi
Masue
M
Department of Hematology and Oncology, Miyagi Children's Hospital, Sendai, Japan.
Matsubara
Yoichi
Y
Department of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Sendai, 980-8574, Japan.
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins; D007951:Leukemia, Myeloid / Q000145:classification / Q000235:genetics*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009634:Noonan Syndrome / Q000201:enzymology / Q000235:genetics*; D010641:Phenotype; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D018909:src Homology Domains
D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases