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Review article
PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase
Rebecca J. Chan1 and Gen-Sheng Feng2,3
1Department
of Pediatrics, the Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis; 2Programs in Signal Transduction and
Stem Cells & Regeneration, Burnham Institute for Medical Research, La Jolla, CA; 3Institute for Biomedical Research, Xiamen University, Xiamen, China
Elucidation of the molecular mechanisms
underlying carcinogenesis has benefited
tremendously from the identification and
characterization of oncogenes and tumor
suppressor genes. One new advance in
this field is the identification of PTPN11
as the first proto-oncogene that encodes
a cytoplasmic tyrosine phosphatase with
2 Src-homology 2 (SH2) domains (Shp2).
This tyrosine phosphatase was previously shown to play an essential role in
normal hematopoiesis. More recently, somatic missense PTPN11 gain-of-function
mutations have been detected in leukemias and rarely in solid tumors, and have
been found to induce aberrant hyperacti-
vation of the Ras-Erk pathway. This
progress represents another milestone in
the leukemia/cancer research field and
provides a fresh view on the molecular
mechanisms underlying cell transformation. (Blood. 2007;109:862-867)
© 2007 by The American Society of Hematology
Introduction
Leukemia and other types of cancer continue to be a leading cause
of death in the United States, and biomedical scientists sorely note
that victories against cancer remain unacceptably rare. Nevertheless, due to the genetic and biochemical analyses of multiple
oncogenes and tumor suppressor genes, significant progress has
been made in understanding the molecular basis for transformation
of a normal cell to a cancer cell. Gain-of-function mutations of
normal cellular genes, termed proto-oncogenes, generate oncogenes that confer a proliferative or survival advantage to the cell. In
contrast, loss-of-function mutations of tumor suppressor genes lead
to dysregulated cellular proliferation and survival.
Reversible phosphorylation of protein tyrosine residues plays a
critical role in signaling cascades for control of cell proliferation,
differentiation, migration, and death. Tyrosyl phosphorylation
levels are determined by the opposing activities of protein tyrosine
kinases (PTKs) and phosphatases (PTPs). Many PTKs are known
to transmit signals resulting in cell proliferation, and thus oncogenic mutations in human cancers commonly target PTKs. Typically, the mutation disrupts the structural integrity of the kinase,
such that autoinhibitory mechanisms are impaired, causing constitutive activation.1 One well-illustrated example is the v-Src oncogene, first identified as an essential oncogenic component in Rous
sarcoma virus. Phosphorylation of tyrosine 527 on the wild-type
(WT) Src induces an intramolecular phosphotyrosine–Src-homology 2 (SH2) interaction and intramolecular contact between the
SH3 domain and the SH2-kinase linker region, both of which
contribute to repression of the kinase activity (Figure 1A).1 v-Src
encodes a constitutively active mutant kinase lacking the Cterminal tail containing Y527 and also possessing missense mutations in the SH3 and kinase domains (Figure 1C).
PTPs conventionally are thought to reverse PTK activities,
thereby attenuating signals for cell proliferation. Although genes
encoding PTPs are strong candidates for tumor suppressor genes,
for example in colorectal cancers,2 few phosphatase genes have
been unequivocally identified as tumor suppressors. Densityenhanced phosphatase 1 (Dep-1) is a receptor PTP that exhibits
tumor suppressor activity when overexpressed in vitro, and Ptprj
maps to the mouse colon cancer susceptibility locus,3 implicating
Ptprj as a potential tumor suppressor gene. Germline PTEN
mutations are found in Cowden syndrome, characterized by
multiple hamartomas and a high proclivity for cancer development,
and somatic loss-of-function PTEN mutations are detected in
several human cancers; however, substantial data suggest that
PTEN mainly acts as a lipid phosphatase, rather than a tyrosine
phosphatase catalytically, and suppresses the phosphoinositide
3-kinase (PI3K) signaling pathway needed for survival and
proliferation.4
Recent studies identified somatic gain-of-function mutations in
PTPN11, which encodes the Shp2 tyrosine phosphatase, in childhood leukemias and, rarely, in adult leukemias and solid tumors.5,6
Similar to multiple mutant tyrosine kinases, the missense PTPN11
mutations destabilize noncovalent interactions between the N-SH2
and PTP domains, resulting in constitutively active phosphatase
activity (Figure 1B,D). Therefore, PTPN11 was identified as the
first proto-oncogene encoding a PTP.
Submitted July 11, 2006; accepted September 17, 2006. Prepublished
online as Blood First Edition Paper, October 19, 2006; DOI 10.1182/blood2006-07-028829.
The online version of this article contains a data supplement.
862
The tyrosine phosphatase Shp2
Shp2 is a widely expressed cytoplasmic PTP containing 2 tandemly
arranged SH2 domains at its amino terminal end, a central
phosphatase domain, and a carboxy terminal tail.7,8 Mice homozygous for a targeted deletion of exon 3, encoding residues 46 to 110
in the N-SH2 domain of Shp2, are embryonic lethal due to
abnormal gastrulation.9 More recently, Yang et al10 showed that
homozygous Shp2 null mutants displayed peri-implantation lethality and that Shp2 had a critical role in trophoblast stem cell
survival. Shp2 associates with activated receptor PTKs or cytokine
receptors, which lack intrinsic kinase activity, either directly by
docking to phosphorylated tyrosine residues on the receptors or
indirectly via adaptor/scaffolding proteins, such as Grb2-associated
© 2007 by The American Society of Hematology
BLOOD, 1 FEBRUARY 2007 䡠 VOLUME 109, NUMBER 3
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BLOOD, 1 FEBRUARY 2007 䡠 VOLUME 109, NUMBER 3
PTPN11, A PTP-ENCODING PROTO-ONCOGENE
863
Figure 1. Schematic diagram of inactive and active forms of Src
kinase (PTK) and Shp2 phosphatase (PTP). (A) c-Src is maintained
in an inactive conformation by intramolecular interactions between
phosphorylated tyrosine 527 on the C-terminal tail and the SH2
domain and between the SH3 domain and the kinase linker region.
Dephosphorylation of tyrosine 527 and binding of a p-Tyr–containing
peptide to the SH2 domain leads to a switch of c-Src to an open
conformation with activation of the kinase function. (B) Deletion of
sequences encoding for tyrosine 527 and missense mutations within
the SH3 or kinase domains (schematically represented by red stars)
converts the c-Src proto-oncogene to an oncogene encoding for
mutant v-Src with constitutive kinase activity. (C) Shp2 is maintained in
an inactive conformation by hydrophobic interactions between amino
acid residues within the N-SH2 domain and the PTP domain. Binding
of a p-Tyr–containing peptide to the N-SH2 domain causes Shp2 to
assume an open conformation with activation of the phosphatase
function. (D) Mutations within the N-SH2 or phosphatase domains
cause disruption of the hydrophobic interactions resulting in constitutive activation of the phosphatase activity. The residues most commonly mutated in childhood leukemias are shown.
binder 1-3 (GAB1-3), fibroblast growth factor receptor substrate-2
(FRS-2), and insulin receptor substrate 1-4 (IRS1-4), all of which
possess 2 conserved tyrosine sites for engagement of the 2 SH2
domains of Shp2.7,8 Genetic and biochemical analyses in Caenorhabditis elegans, Drosophila, Xenopus, and mammals support the
notion that Shp2 promotes Ras activation by growth factors and
cytokines.11-18 Although different models have been proposed
involving phosphatase-dependent and -independent mechanisms,
most functional analyses suggest that the catalytic activity of Shp2
is required for promotion of signaling through the Ras-Erk
pathway. Several studies suggest that Shp2 dephosphorylates, and
thus inhibits, RasGAP and sprouty proteins, both negative regulators of Ras activation.8,19 Alternatively, Shp2 has been proposed to
lead to the dephosphorylation of Src kinase, either directly or
indirectly, leading to Src activation with subsequent Ras activation.8,20 However, the unequivocal identification of Shp2 substrates
continues to be sought.
Shp2 enzymatic studies revealed low basal phosphatase activity
with rapid induction upon occupancy of the SH2 domains.21-24
Consistently, the crystal structure of Shp2 revealed direct contact
between the N-SH2 domain and the catalytic domain, constituting
an autoinhibitory effect (Figure 1B).25 Occupation of the N-SH2
domain by a phosphotyrosine (p-Tyr)–containing ligand alleviates
the autoinhibition, and therefore, association of Shp2 with a
regulatory protein is directly coupled to phosphatase activation
(Figure 1B). Importantly, the N-SH2 residues that interact with
the PTP domain are not part of the p-Tyr–binding pocket.
Therefore, mutation of catalytic domain-interacting residues
within the N-SH2 domain (Figure 1D) will generate a molecule
with enhanced phosphatase activity and retained capacity to
bind p-Tyr–containing proteins. Indeed, Neel’s group26 has
demonstrated this principle in Xenopus embryo animal cap
elongation studies.
Role of Shp2 in hematopoiesis
In contrast to Shp1, which has a negative regulatory role in
myeloid/lymphoid cell development and functions, Shp2 has been
found to be essential for normal hematopoietic cell development.27-30 In an in vitro hematopoietic differentiation assay, homozygous mutant embryonic stem (ES) cells for the Shp2⌬46-110 deletion
mutation exhibited severely decreased differentiation capacity to
erythroid and myeloid progenitors.27 This in vitro result was
supported by the in vivo chimeric animal analysis, in which neither
erythroid nor myeloid progenitor cells of Shp2⌬46-110 origin were
detected in the fetal liver or bone marrow of chimeric animals that
were derived from mutant ES cells and wild-type embryos.28
Notably, Shp2 mutant ES cells did have significant contributions to
many other organs or tissues of the chimeras, suggesting a more
stringent requirement for Shp2 in hematopoiesis than development
of many other cell types in mammals.28 A RAG-2–deficient
blastocyst complementation assay further demonstrated a critical
role of Shp2 for lymphopoiesis in a cell-autonomous manner, as
development of lymphoid cell lineages in Shp2⫺/⫺/Rag-2⫺/⫺ chimeric mice was blocked before pro-T- and pro-B-cell stages.29
Thus, Shp2 is positively required for development of all hematopoietic cell lineages, suggesting a role of Shp2 in the commitment/
differentiation of hematopoietic stem cells.
Indeed, experimental data suggest that lack of normal Shp2
function leads to decreased differentiation from ES cells to
hemangioblasts (BL-CFC),30 a multipotential precursor that has the
capacity to differentiate into primitive and definitive erythroid cells
as well as endothelial cells.31,32 Consistently, Shp2 mutant ES cells
displayed decreased and delayed expression of brachyury and flk-1,
markers of mesoderm and endothelial cells, respectively, upon
differentiation in vitro.30 Shp2 appears to play a positive role in
promoting the Erk pathway and a negative role in the Jak/Stat3
pathway in control of stem cell self-renewal and differentiation. In
factor-dependent hematopoietic cell lines, Shp2 has been shown to
participate in the relay of signals elicited by interleukin-6 (IL-6),
leukemia inhibitory factor (LIF), IL-3/granulocyte macrophage–
colony-stimulating factor (GM-CSF), erythropoietin (Epo), or stem
cell factor (SCF).33-36 Functional analysis suggests that Shp2 may
act in both a catalytic-dependent and -independent manner in
mediating IL-3–stimulated proliferation and survival of hematopoietic cells.37
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864
CHAN and FENG
BLOOD, 1 FEBRUARY 2007 䡠 VOLUME 109, NUMBER 3
tions are also found in Noonanlike/multiple giant cell lesion
syndrome, which clinically can be confused with cherubism.41,45,46
Notably, PTPN11 mutations have not been identified in the
phenotypically overlapping cardio-facio-cutaneous (CFC) or
Costello syndromes39; however, recent reports reveal HRAS mutations in Costello syndrome,47 KRAS, BRAF, MEK1, or MEK2
mutations in CFC syndrome,48,49 and KRAS mutations in a small
percentage of patients with NS,50,51 implicating the common theme
of aberrant Ras-Erk signaling in these overlapping human developmental disorders (Figure 3). Consistent with this, neurofibromatosis type 1 (NF1), which results from loss-of-function mutations in
neurofibromin, a GTPase activating protein (GAP) that accelerates
the conversion of active Ras-GTP to inactive Ras-GDP, shares
clinical similarities with NS, including neurofibromas, neural
crest–derived malignant tumors, cardiac anomalies, and JMML.52
Somatic PTPN11 mutations in leukemia
Figure 2. Graphic representation of mutation prevalence among individuals
bearing PTPN11 mutations with Noonan syndrome (NS), childhood leukemia,
and LEOPARD syndrome (LS). (A) PTPN11 mutations observed in NS are
distributed widely throughout the PTPN11 gene, with the most common affected
residue being glutamine (N) 308 (based on 175 patients with NS identified with
PTPN11 mutations). (B) PTPN11 mutations observed in childhood leukemias are
clustered within exons 3 and 13 (based on 163 patients with pediatric leukemia
identified with PTPN11 mutations). (C) The vast majority of PTPN11 mutations
observed in LS involve residues tyrosine (Y) 279 and threonine (T) 468 (based on 63
patients with LS identified with PTPN11 mutations).
The observation that JMML, a rare form of childhood leukemia,
was observed in patients with NS, predicted that individuals with
nonsyndromic JMML may bear somatic PTPN11 mutations. Indeed, after identification of germ line mutations of PTPN11 in
patients with NS,38 Tartaglia and colleagues5 also pioneered the
search of somatic PTPN11 mutations in individuals with nonsyndromic JMML. Collectively, recent studies by several groups
indicate that somatic mutations within PTPN11 occur in 35% of
JMML cases, as well as in childhood acute myeloid leukemia (4%),
myelodysplastic syndrome (10%), and acute lymphoid leukemia
(7%).5,53-59 While germ line mutations found in NS occur in
multiple exons throughout PTPN11 (Figure 2A and Table S1,
which is available on the Blood website; see the Supplemental
Table link at the top of the online article), pediatric leukemiaassociated mutations (both syndromic and nonsyndromic) are
concentrated in exons 3 and 13 (Figure 2B and Table S1). Mutation
of residues glycine 60, aspartate 61, glutamate 69, alanine 72,
glutamate 76, all encoded by exon 3, accounts for approximately
83% of the PTPN11 mutations observed in all pediatric leukemias
combined. The most common mutation found in individuals with
Germline PTPN11 mutations in Noonan
syndrome and related congenital disorders
The significance of Shp2 in human disease became evident when
PTPN11 germ line mutations were identified in individuals with
Noonan syndrome (NS), an autosomal dominant disorder with an
estimated incidence of 1 in 2500 live births.38,39 The most common
abnormalities are dysmorphic facial features, heart defects, skeletal
abnormalities, and growth retardation.39 Hematologic abnormalities, including hepatosplenomegaly unexplained by cardiac failure
(25%-50%) and, rarely, aggressive juvenile myelomonocytic leukemia (JMML), are also observed in patients with NS.40 Based on
genotyping data, the most commonly mutated residue in NS is
asparagine 308 (26%) followed by tyrosine 63 (12%) and glutamine 79 (8.5%; Figure 2A).39,41,42 Individuals with generalized
lentigines are classified into a Noonanlike syndrome called LEOPARD (multiple lentigines, electrocardiographic-conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, sensorineural deafness) syndrome
(LS). PTPN11 mutations are observed in approximately 90% of
patients with LS, with 85% of the mutations involving residues
tyrosine 279 or threonine 468 (Figure 2C).39,43,44 PTPN11 muta-
Figure 3. Schematic diagram showing ligand-stimulated Ras activation, the
Ras-Erk pathway, and the human diseases found to date associated with
mutation of multiple molecules participating in this signaling cascade. NL/
MGCL indicates Noonanlike/multiple giant cell lesion; CFC, cardio-facio-cutaneous;
JMML, juvenile myelomonocytic leukemia.
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BLOOD, 1 FEBRUARY 2007 䡠 VOLUME 109, NUMBER 3
NS and associated myeloproliferative disease (MPD) is T73I
(42.1% of reported cases).5,53,55,56 T73I, along with D61G, are the
only mutations found in NS,39 NS in association with MPD,5,53,55,56
and de novo, nonsyndromic leukemia.53,54
Functional and phenotypic implications
of PTPN11 mutations
Comparison of PTPN11 germ line mutations observed in patients
with NS to somatic mutations identified in individuals with
nonsyndromic leukemia reveals that the 2 groups are largely
nonoverlapping (exceptions include G60A, D61G, D61N, F71L,
T73I, E139D, and R498W; Table S1). This observation prompted
the notion that increasingly higher levels of phosphatase activity
induce more severe phenotypes and that the most functionally
severe mutations may induce in utero lethality if sustained in the
germ line.60 This hypothesis is supported by the finding that the
leukemia-associated PTPN11 mutants D61Y and E76K encode for
mutant Shp2 with very high basal and unregulated phosphatase
activity.5,56,60,61 Consistently, mutations observed in NS, syndromic
leukemia, or nonsyndromic leukemia (D61G and T73I) encode for
mutant Shp2 with high basal, yet p-Tyr-peptide–inducible phosphatase activity.61 Germ line mutations observed only in patients with
NS (N308D) encode mutant Shp2 with only modestly high basal
phosphatase activity.5,56,61 However, this correlation does not hold
true for all the mutant Shp2 proteins examined. Keilhack et al61
determined that p-Tyr-peptide affinity, in contrast to absolute
phosphatase activity, also contributes to the gain-of-function effect
of some Shp2 mutants. Moreover, Niihori et al56 observed that 2
mutations found only in NS (D61N and F71I) had higher relative
phosphatase activity than 2 mutations found in nonsyndromic
leukemia (E76A and G503V).
Recent findings further highlight the difficulty in predicting a
disease phenotype based merely on in vitro phosphatase activity
assay. Surprisingly, PTPN11 mutations observed in LEOPARD
syndrome (Y279C and T468M) reduce Shp2 phosphatase activity
in vitro and inhibit ligand-stimulated phospho-Erk activation in
cells, in contrast to the gain-of-function mutations observed in
NS.60,62 However, the Shp2 crystal structure predicts that the
Y279C and T468M mutant proteins reside preferentially in the
open conformation, suggesting that these mutant proteins may
exert defective signaling in vivo due to aberrant adapter function in
assembling multiprotein signaling complexes or due to competition
with WT Shp2 for substrates.
Functional and signal transduction
alternations induced by PTPN11 mutations
JMML is a rare clonal MPD of children younger than 5 years of age
and is characterized clinically by hepatosplenomegaly, increased
circulating monocytes and erythroblasts, and increased production
of fetal hemoglobin (HbF), implying a regression to fetallike
hematopoiesis.63 In vitro, hematopoietic progenitors from patients
with JMML demonstrate hypersensitivity to GM-CSF.64 Hyperactivation of Ras is implicated in the pathogenesis of JMML based on
the identification of activating NRAS and KRAS mutations65,66 and
loss-of-heterozygosity of NF1 in patient samples (Figure 3).67
Well-studied molecular mechanisms leading to JMML in humans
with NF1 and in animal models bearing Nf1 loss-of-function or
activating Kras mutations are instructive when considering the
potential molecular aberrations induced by activating PTPN11
PTPN11, A PTP-ENCODING PROTO-ONCOGENE
865
mutations. Biochemical analysis of primary leukemic cells from
patients with NF1 demonstrates increased levels of Ras-GTP and
Erk hyperactivation.68 Likewise, hematopoietic progenitors from
⫺/⫺
Nf1 and KrasG12D mice demonstrate elevated Ras-GTP, hypersensitivity to GM-CSF, and induce MPD in vivo.69-71 Conditional
inactivation of Nf1 in hematopoietic cells induces MPD with 100%
penetrance, hypersensitivity to GM-CSF, and resistance to apoptosis.72 Likewise, wild-type mice reconstituted with fetal liver
progenitors from Nf1⫺/⫺ animals develop MPD similar to JMML,
which is attenuated in mice lacking GM-CSF; however, despite a
longer latency, some mice lacking GM-CSF eventually succumb to
MPD.73 These findings highlight that although crucial, dysregulated GM-CSF signaling alone likely is not sufficient to induce
JMML. Indeed, hematopoietic progenitors from KrasG12D and
Nf1⫺/⫺ mice also demonstrate hypersensitivity to IL-369 and IL-3
plus stem cell factor,74 respectively. Recognizing and understanding the relevance of additional hematopoietic growth factor pathways in JMML pathogenesis is imperative for the successful
development of novel therapeutic strategies in this disease.
Retroviral transduction of 3 commonly observed somatic
PTPN11 mutants (E76K, D61V, and D61Y) into murine bone
marrow– or fetal liver–derived mononuclear cells induces hematopoietic progenitor hypersensitivity to GM-CSF, similar to that
observed in patients with JMML, as well as to IL-3.75-77 Likewise,
transduction of bone marrow– or fetal liver–derived mononuclear
cells with mutant E76K results in a significant increase in erythroid
burst-forming unit (BFU-E) colonies, consistent with increased
circulating erythroblasts observed in patients with JMML.77 Macrophage progenitors bearing the E76K, D61Y, or D61V mutants
hyperproliferate in response to GM-CSF, and each mutation
induced elevated constitutive and prolonged GM-CSF–stimulated
phospho-Erk activation.75 Additionally, IL-3 stimulation of mutantbearing mast cells promoted hyperproliferation and induced hyperactivation of phospho-Akt and phospho-Stat5.76 Structure-function
studies defined that ablation of the phosphatase function (by both
C463S or R465M mutations), impairment of binding activity of the
N-SH2 domain or C-SH2 domains, or mutation of tyrosine 542,
severely abrogated the transforming ability of the E76K mutant,76,77 suggesting that both the enzymatic function as well as the
adapter function of Shp2 substantially contribute to the transforming ability of the Shp2 mutants.
Approximately 50% of mice reconstituted with hematopoietic
progenitors transduced with PTPN11 mutants E76K or D61Y
succumbed to malignant hematologic disease by 7 months after
transplantation. At death, the majority of mice were found to bear a
severe MPD, including hepatosplenomegaly and bone marrow
hyperplasia with increased immature myelomonocytic cells.76 This
progressive, lethal form of MPD is in contrast to the later-onset,
nonlethal, chronic myelomonocytic hyperplasia observed in a
mouse model bearing the common NS germ line PTPN11 mutation,
D61G.78 This variable transforming ability of the different PTPN11
mutants in part rationalizes the unpredictable clinical course of
JMML in patients with NS bearing germ line PTPN11 mutations,
which spans from mild disease ending in spontaneous remission to
progressive cases ending in death.40
One peculiar observation is that the incidence of somatic
PTPN11 mutations is higher in JMML compared with acute
leukemias and solid tumors. A contributing factor to this phenomenon may be the cell population targeted by PTPN11 mutations
leading to JMML. A recent study examining a GATA1 mutation
found in individuals with Down syndrome and transient MPD or
acute megakaryoblastic leukemia revealed a novel embryonic
progenitor population targeted by this mutation.79 Similarly, fetal
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BLOOD, 1 FEBRUARY 2007 䡠 VOLUME 109, NUMBER 3
CHAN and FENG
myeloid progenitors may be exceptionally sensitive to the effects of
activating PTPN11 mutations compared with those of adult myeloid progenitors. Interaction with a second, cooperating mutation
or modifier loci may be required for clonal outgrowth progressing
to frank JMML, while the absence of these functional genetic
interactions may allow for the spontaneous remission of JMML, as
observed in some patients with NS with germ line PTPN11
mutations.40 Although speculative, this hypothesis is consistent
with the finding that murine transplantation of PTPN11 mutant–
bearing cells produced robust MPD on the Balb/c background and
only subtle abnormalities on the C57Bl/6 background.76,77
Although PTPN11 mutations are found only rarely in adult
leukemias,80-82 recent studies demonstrate elevated Shp2 expression in primary leukemia cell specimens from multiple adult acute
leukemias, compared with Shp2 levels in bone marrow mononuclear cells from healthy controls.82 Upon terminal differentiation, Shp2 expression diminished, suggesting that persistently
elevated Shp2 expression may lead to perturbations in hematopoietic cell differentiation.82 Consistently, overexpression of WT Shp2
inhibited macrophage progenitor differentiation in response to
macrophage colony-stimulating factor (M-CSF) based on F4/80
expression,75 suggesting that excessive Shp2 may inhibit or delay
the maturation of myeloid progenitors, contributing to
leukemogenesis.
scope of oncogenes, but also refresh our views on the critical
difference between proto-oncogenes and oncogenes mediating
either physiologic regulation or pathologic dysregulation in normal
cells and malignant cells, respectively. One important functional
consequence of activating PTPN11 or KRAS mutations or loss-offunction NF1 mutations is Ras hyperactivation; therefore, Ras
effectors, such as Mek and PI3K, are rational targets for novel
therapeutics in JMML. Indeed, in vitro treatment of hematopoietic
progenitors with the Mek inhibitor, UO126, or with rapamycin, an
inhibitor of the PI3K-mTOR pathway, reduces the transforming
ability of PTPN11 mutant E76K.76 The current challenge entails
building on this broad fund of knowledge to define novel molecular
targets with the objective of developing improved therapeutics for
pediatric and adult myeloid leukemias.
Acknowledgments
The authors wish to acknowledge the tenacious genotyping work of
multiple investigators reviewed by Tartaglia and Gelb.39 Additionally, the authors thank Dr Mignon Loh for helpful discussion in the
presentation of the genotyping data. Work in authors’ laboratories
was supported by the March of Dimes (Basil O’Connor Starter
Scholar Award, R.J.C.) and the National Institutes of Health
(RO1HL082 981, R.J.C.; CA078 606 and CA102 583, G.-S.F.).
Conclusion
Authorship
Based on genotyping studies, in vitro and in vivo functional
studies, and enzymatic studies, PTPN11 is the first identified
proto-oncogene that encodes a PTP. Strikingly, a similar molecular
mechanism is employed in oncogenic activation of an intracellular
PTK (c-Src) or a PTP (Shp2), which involves disruption of an
autoinhibitory intramolecular interaction leading to constitutive
activation. Thus, the studies on mutant Shp2 not only expand the
Contribution: R.J.C. and G.-S.F. wrote and revised the paper.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Correspondence: Gen-Sheng Feng, Burnham Institute for Medical Research, 10901 N Torrey Pines Rd, La Jolla, CA 92037;
e-mail: [email protected].
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2007 109: 862-867
doi:10.1182/blood-2006-07-028829 originally published
online October 19, 2006
PTPN11 is the first identified proto-oncogene that encodes a tyrosine
phosphatase
Rebecca J. Chan and Gen-Sheng Feng
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