Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis.
The PTPN11 gene encodes SHP-2 (Src homology 2 domain-containing protein tyrosine Phosphatase), a nonreceptor tyrosine protein tyrosine phosphatase (PTPase) that relays signals from activated growth factor receptors to p21Ras (Ras) and other signaling molecules. Mutations in PTPN11 cause Noonan syndrome (NS), a developmental disorder characterized by cardiac and skeletal defects. NS is also associated with a spectrum of hematologic disorders, including juvenile myelomonocytic leukemia (JMML). To test the hypothesis that PTPN11 mutations might contribute to myeloid leukemogenesis, we screened the entire coding region for mutations in 51 JMML specimens and in selected exons from 60 patients with other myeloid malignancies. Missense mutations in PTPN11 were detected in 16 of 49 JMML specimens from patients without NS, but they were less common in other myeloid malignancies. RAS, NF1, and PTPN11 mutations are largely mutually exclusive in JMML, which suggests that mutant SHP-2 proteins deregulate myeloid growth through Ras. However, although Ba/F3 cells engineered to express leukemia-associated SHP-2 proteins cells showed enhanced growth factor-independent survival, biochemical analysis failed to demonstrate hyperactivation of the Ras effectors extracellular-regulated kinase (ERK) or Akt. We conclude that SHP-2 is an important cellular PTPase that is mutated in myeloid malignancies. Further investigation is required to clarify how these mutant proteins interact with Ras and other effectors to deregulate myeloid growth.
Loh
Mignon L
ML
Department of Pediatrics, University of California, Rm HSE-302 Box 0519, San Francisco, CA 94143, USA. lohm@itsa.ucsf.edu
Vattikuti
Shashaank
S
Schubbert
Suzanne
S
Reynolds
Melissa G
MG
Carlson
Elaine
E
Lieuw
Kenneth H
KH
Cheng
Jennifer W
JW
Lee
Connie M
CM
Stokoe
David
D
Bonifas
Jeannette M
JM
Curtiss
Nicole P
NP
Gotlib
Jason
J
Meshinchi
Soheil
S
Le Beau
Michelle M
MM
Emanuel
Peter D
PD
Shannon
Kevin M
KM
D000595:Amino Acid Sequence; D002478:Cells, Cultured; D002648:Child; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007951:Leukemia, Myeloid / Q000235:genetics; D015477:Leukemia, Myelomonocytic, Chronic / Q000235:genetics*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D025542:Neurofibromin 1 / Q000235:genetics; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D018631:ras Proteins / Q000378:metabolism
D047908:Intracellular Signaling Peptides and Proteins; D025542:Neurofibromin 1; D011518:Proto-Oncogene Proteins; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; D018631:ras Proteins