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Review article

PTPN11 is the first identified proto- that encodes a

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 2 Src-homology 2 (SH2) domains (Shp2). vation of the Ras-Erk pathway. This underlying carcinogenesis has benefited This tyrosine phosphatase was previ- progress represents another milestone in tremendously from the identification and ously shown to play an essential role in the leukemia/cancer research field and characterization of and tumor normal hematopoiesis. More recently, so- provides a fresh view on the molecular suppressor . One new advance in matic missense PTPN11 gain-of-function mechanisms underlying cell transforma- this field is the identification of PTPN11 mutations have been detected in leuke- tion. (Blood. 2007;109:862-867) as the first proto-oncogene that encodes mias and rarely in solid tumors, and have a cytoplasmic tyrosine phosphatase with been found to induce aberrant hyperacti- © 2007 by The American Society of Hematology Introduction

Leukemia and other types of cancer continue to be a leading cause tumor suppressor activity when overexpressed in vitro, and Ptprj of death in the United States, and biomedical scientists sorely note maps to the mouse colon cancer susceptibility ,3 implicating that victories against cancer remain unacceptably rare. Neverthe- Ptprj as a potential tumor suppressor . Germline PTEN less, due to the genetic and biochemical analyses of multiple mutations are found in , characterized by oncogenes and tumor suppressor genes, significant progress has multiple hamartomas and a high proclivity for cancer development, been made in understanding the molecular basis for transformation and somatic loss-of-function PTEN mutations are detected in of a normal cell to a cancer cell. Gain-of-function mutations of several human cancers; however, substantial data suggest that normal cellular genes, termed proto-oncogenes, generate onco- PTEN mainly acts as a lipid phosphatase, rather than a tyrosine genes that confer a proliferative or survival advantage to the cell. In phosphatase catalytically, and suppresses the phosphoinositide contrast, loss-of-function mutations of tumor suppressor genes lead 3-kinase (PI3K) signaling pathway needed for survival and to dysregulated cellular proliferation and survival. proliferation.4 Reversible phosphorylation of tyrosine residues plays a Recent studies identified somatic gain-of-function mutations in critical role in signaling cascades for control of cell proliferation, PTPN11, which encodes the Shp2 tyrosine phosphatase, in child- differentiation, migration, and death. Tyrosyl phosphorylation hood leukemias and, rarely, in adult leukemias and solid tumors.5,6 levels are determined by the opposing activities of protein tyrosine Similar to multiple mutant tyrosine kinases, the missense PTPN11 kinases (PTKs) and (PTPs). Many PTKs are known mutations destabilize noncovalent interactions between the N-SH2 to transmit signals resulting in cell proliferation, and thus onco- and PTP domains, resulting in constitutively active phosphatase genic mutations in human cancers commonly target PTKs. Typi- activity (Figure 1B,D). Therefore, PTPN11 was identified as the cally, the mutation disrupts the structural integrity of the kinase, first proto-oncogene encoding a PTP. such that autoinhibitory mechanisms are impaired, causing consti- tutive activation.1 One well-illustrated example is the v-Src onco- gene, first identified as an essential oncogenic component in Rous sarcoma virus. Phosphorylation of tyrosine 527 on the wild-type The tyrosine phosphatase Shp2 (WT) Src induces an intramolecular phosphotyrosine–Src-homol- ogy 2 (SH2) interaction and intramolecular contact between the Shp2 is a widely expressed cytoplasmic PTP containing 2 tandemly SH3 domain and the SH2-kinase linker region, both of which arranged SH2 domains at its amino terminal end, a central contribute to repression of the kinase activity (Figure 1A).1 v-Src phosphatase domain, and a carboxy terminal tail.7,8 Mice homozy- encodes a constitutively active mutant kinase lacking the C- gous for a targeted deletion of exon 3, encoding residues 46 to 110 terminal tail containing Y527 and also possessing missense muta- in the N-SH2 domain of Shp2, are embryonic lethal due to tions in the SH3 and kinase domains (Figure 1C). abnormal gastrulation.9 More recently, Yang et al10 showed that PTPs conventionally are thought to reverse PTK activities, homozygous Shp2 null mutants displayed peri-implantation lethal- thereby attenuating signals for cell proliferation. Although genes ity and that Shp2 had a critical role in trophoblast stem cell encoding PTPs are strong candidates for tumor suppressor genes, survival. Shp2 associates with activated PTKs or cytokine for example in colorectal cancers,2 few phosphatase genes have receptors, which lack intrinsic kinase activity, either directly by been unequivocally identified as tumor suppressors. Density- docking to phosphorylated tyrosine residues on the receptors or enhanced phosphatase 1 (Dep-1) is a receptor PTP that exhibits indirectly via adaptor/scaffolding , such as Grb2-associated

Submitted July 11, 2006; accepted September 17, 2006. Prepublished The online version of this article contains a data supplement. online as Blood First Edition Paper, October 19, 2006; DOI 10.1182/blood- 2006-07-028829. © 2007 by The American Society of Hematology

862 BLOOD, 1 FEBRUARY 2007 ⅐ VOLUME 109, NUMBER 3 From www.bloodjournal.org by guest on July 4, 2016. For personal use only.

BLOOD, 1 FEBRUARY 2007 ⅐ 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 constitu- tive activation of the phosphatase activity. The residues most com- monly mutated in childhood leukemias are shown.

binder 1-3 (GAB1-3), fibroblast growth factor receptor substrate-2 found to be essential for normal hematopoietic cell develop- (FRS-2), and receptor substrate 1-4 (IRS1-4), all of which ment.27-30 In an in vitro hematopoietic differentiation assay, homozy- possess 2 conserved tyrosine sites for engagement of the 2 SH2 gous mutant embryonic stem (ES) cells for the Shp2⌬46-110 deletion domains of Shp2.7,8 Genetic and biochemical analyses in Caeno- mutation exhibited severely decreased differentiation capacity to rhabditis elegans, Drosophila, Xenopus, and mammals support the erythroid and myeloid progenitors.27 This in vitro result was notion that Shp2 promotes Ras activation by growth factors and supported by the in vivo chimeric animal analysis, in which neither cytokines.11-18 Although different models have been proposed erythroid nor myeloid progenitor cells of Shp2⌬46-110 origin were involving phosphatase-dependent and -independent mechanisms, detected in the fetal liver or bone marrow of chimeric animals that most functional analyses suggest that the catalytic activity of Shp2 were derived from mutant ES cells and wild-type embryos.28 is required for promotion of signaling through the Ras-Erk Notably, Shp2 mutant ES cells did have significant contributions to pathway. Several studies suggest that Shp2 dephosphorylates, and many other organs or tissues of the chimeras, suggesting a more thus inhibits, RasGAP and sprouty proteins, both negative regula- stringent requirement for Shp2 in hematopoiesis than development tors of Ras activation.8,19 Alternatively, Shp2 has been proposed to of many other cell types in mammals.28 A RAG-2–deficient lead to the dephosphorylation of Src kinase, either directly or blastocyst complementation assay further demonstrated a critical indirectly, leading to Src activation with subsequent Ras activa- role of Shp2 for lymphopoiesis in a cell-autonomous manner, as tion.8,20 However, the unequivocal identification of Shp2 substrates development of lymphoid cell lineages in Shp2Ϫ/Ϫ/Rag-2Ϫ/Ϫ chi- continues to be sought. 29 Shp2 enzymatic studies revealed low basal phosphatase activity meric mice was blocked before pro-T- and pro-B-cell stages. with rapid induction upon occupancy of the SH2 domains.21-24 Thus, Shp2 is positively required for development of all hematopoi- Consistently, the crystal structure of Shp2 revealed direct contact etic cell lineages, suggesting a role of Shp2 in the commitment/ between the N-SH2 domain and the catalytic domain, constituting differentiation of hematopoietic stem cells. an autoinhibitory effect (Figure 1B).25 Occupation of the N-SH2 Indeed, experimental data suggest that lack of normal Shp2 domain by a phosphotyrosine (p-Tyr)–containing alleviates function leads to decreased differentiation from ES cells to the autoinhibition, and therefore, association of Shp2 with a hemangioblasts (BL-CFC),30 a multipotential precursor that has the regulatory protein is directly coupled to phosphatase activation capacity to differentiate into primitive and definitive erythroid cells (Figure 1B). Importantly, the N-SH2 residues that interact with as well as endothelial cells.31,32 Consistently, Shp2 mutant ES cells the PTP domain are not part of the p-Tyr–binding pocket. displayed decreased and delayed expression of brachyury and flk-1, Therefore, mutation of catalytic domain-interacting residues markers of mesoderm and endothelial cells, respectively, upon within the N-SH2 domain (Figure 1D) will generate a molecule differentiation in vitro.30 Shp2 appears to play a positive role in with enhanced phosphatase activity and retained capacity to promoting the Erk pathway and a negative role in the Jak/Stat3 bind p-Tyr–containing proteins. Indeed, Neel’s group26 has pathway in control of stem cell self-renewal and differentiation. In demonstrated this principle in Xenopus embryo animal cap factor-dependent hematopoietic cell lines, Shp2 has been shown to elongation studies. 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 Role of Shp2 in hematopoiesis cell factor (SCF).33-36 Functional analysis suggests that Shp2 may act in both a catalytic-dependent and -independent manner in In contrast to Shp1, which has a negative regulatory role in mediating IL-3–stimulated proliferation and survival of hematopoi- myeloid/lymphoid cell development and functions, Shp2 has been etic cells.37 From www.bloodjournal.org by guest on July 4, 2016. For personal use only.

864 CHAN and FENG BLOOD, 1 FEBRUARY 2007 ⅐ VOLUME 109, NUMBER 3

tions are also found in Noonanlike/multiple giant cell lesion syndrome, which clinically can be confused with .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 muta- tions in ,47 KRAS, BRAF, MEK1,orMEK2 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 develop- mental disorders (Figure 3). Consistent with this, neurofibromato- sis 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

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. In- deed, 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 nonsyn- dromic JMML. Collectively, recent studies by several groups indicate that somatic mutations within PTPN11 occur in 35% of JMML cases, as well as in childhood (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, Figure 2. Graphic representation of mutation prevalence among individuals which is available on the Blood website; see the Supplemental bearing PTPN11 mutations with (NS), childhood leukemia, Table link at the top of the online article), pediatric leukemia- and LEOPARD syndrome (LS). (A) PTPN11 mutations observed in NS are distributed widely throughout the PTPN11 gene, with the most common affected associated mutations (both syndromic and nonsyndromic) are residue being glutamine (N) 308 (based on 175 patients with NS identified with concentrated in exons 3 and 13 (Figure 2B and Table S1). Mutation PTPN11 mutations). (B) PTPN11 mutations observed in childhood leukemias are of residues glycine 60, aspartate 61, glutamate 69, alanine 72, clustered within exons 3 and 13 (based on 163 patients with pediatric leukemia identified with PTPN11 mutations). (C) The vast majority of PTPN11 mutations glutamate 76, all encoded by exon 3, accounts for approximately observed in LS involve residues tyrosine (Y) 279 and threonine (T) 468 (based on 63 83% of the PTPN11 mutations observed in all pediatric leukemias patients with LS identified with PTPN11 mutations). 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 abnormali- ties, including hepatosplenomegaly unexplained by cardiac failure (25%-50%) and, rarely, aggressive juvenile myelomonocytic leuke- mia (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 glu- tamine 79 (8.5%; Figure 2A).39,41,42 Individuals with generalized lentigines are classified into a Noonanlike syndrome called LEOP- ARD (multiple lentigines, electrocardiographic-conduction abnor- malities, ocular hypertelorism, pulmonary stenosis, abnormal geni- talia, retardation of growth, sensorineural deafness) syndrome Figure 3. Schematic diagram showing ligand-stimulated Ras activation, the (LS). PTPN11 mutations are observed in approximately 90% of Ras-Erk pathway, and the human diseases found to date associated with mutation of multiple molecules participating in this signaling cascade. NL/ patients with LS, with 85% of the mutations involving residues MGCL indicates Noonanlike/multiple giant cell lesion; CFC, cardio-facio-cutaneous; tyrosine 279 or threonine 468 (Figure 2C).39,43,44 PTPN11 muta- JMML, juvenile myelomonocytic leukemia. From www.bloodjournal.org by guest on July 4, 2016. For personal use only.

BLOOD, 1 FEBRUARY 2007 ⅐ VOLUME 109, NUMBER 3 PTPN11, A PTP-ENCODING PROTO-ONCOGENE 865

NS and associated myeloproliferative disease (MPD) is T73I mutations. Biochemical analysis of primary leukemic cells from (42.1% of reported cases).5,53,55,56 T73I, along with D61G, are the patients with NF1 demonstrates increased levels of Ras-GTP and only mutations found in NS,39 NS in association with MPD,5,53,55,56 Erk hyperactivation.68 Likewise, hematopoietic progenitors from Ϫ Ϫ and de novo, nonsyndromic leukemia.53,54 Nf1 / and KrasG12D mice demonstrate elevated Ras-GTP, hypersen- sitivity to GM-CSF, and induce MPD in vivo.69-71 Conditional inactivation of Nf1 in hematopoietic cells induces MPD with 100% Functional and phenotypic implications penetrance, hypersensitivity to GM-CSF, and resistance to apopto- of PTPN11 mutations sis.72 Likewise, wild-type mice reconstituted with fetal liver progenitors from Nf1Ϫ/Ϫ animals develop MPD similar to JMML, Comparison of PTPN11 germ line mutations observed in patients which is attenuated in mice lacking GM-CSF; however, despite a with NS to somatic mutations identified in individuals with longer latency, some mice lacking GM-CSF eventually succumb to nonsyndromic leukemia reveals that the 2 groups are largely MPD.73 These findings highlight that although crucial, dysregu- nonoverlapping (exceptions include G60A, D61G, D61N, F71L, lated GM-CSF signaling alone likely is not sufficient to induce T73I, E139D, and R498W; Table S1). This observation prompted JMML. Indeed, hematopoietic progenitors from KrasG12D and the notion that increasingly higher levels of phosphatase activity Nf1Ϫ/Ϫ mice also demonstrate hypersensitivity to IL-369 and IL-3 induce more severe and that the most functionally plus stem cell factor,74 respectively. Recognizing and understand- severe mutations may induce in utero lethality if sustained in the ing the relevance of additional hematopoietic growth factor path- germ line.60 This hypothesis is supported by the finding that the ways in JMML pathogenesis is imperative for the successful leukemia-associated PTPN11 mutants D61Y and E76K encode for development of novel therapeutic strategies in this disease. mutant Shp2 with very high basal and unregulated phosphatase Retroviral transduction of 3 commonly observed somatic activity.5,56,60,61 Consistently, mutations observed in NS, syndromic PTPN11 mutants (E76K, D61V, and D61Y) into murine bone leukemia, or nonsyndromic leukemia (D61G and T73I) encode for marrow– or fetal liver–derived mononuclear cells induces hemato- mutant Shp2 with high basal, yet p-Tyr-peptide–inducible phospha- poietic progenitor hypersensitivity to GM-CSF, similar to that tase activity.61 Germ line mutations observed only in patients with observed in patients with JMML, as well as to IL-3.75-77 Likewise, NS (N308D) encode mutant Shp2 with only modestly high basal transduction of bone marrow– or fetal liver–derived mononuclear phosphatase activity.5,56,61 However, this correlation does not hold cells with mutant E76K results in a significant increase in erythroid true for all the mutant Shp2 proteins examined. Keilhack et al61 burst-forming unit (BFU-E) colonies, consistent with increased determined that p-Tyr-peptide affinity, in contrast to absolute circulating erythroblasts observed in patients with JMML.77 Macro- phosphatase activity, also contributes to the gain-of-function effect phage progenitors bearing the E76K, D61Y, or D61V mutants of some Shp2 mutants. Moreover, Niihori et al56 observed that 2 hyperproliferate in response to GM-CSF, and each mutation mutations found only in NS (D61N and F71I) had higher relative induced elevated constitutive and prolonged GM-CSF–stimulated phosphatase activity than 2 mutations found in nonsyndromic phospho-Erk activation.75 Additionally, IL-3 stimulation of mutant- leukemia (E76A and G503V). bearing mast cells promoted hyperproliferation and induced hyper- Recent findings further highlight the difficulty in predicting a activation of phospho-Akt and phospho-Stat5.76 Structure-function disease based merely on in vitro phosphatase activity studies defined that ablation of the phosphatase function (by both assay. Surprisingly, PTPN11 mutations observed in LEOPARD C463S or R465M mutations), impairment of binding activity of the syndrome (Y279C and T468M) reduce Shp2 phosphatase activity N-SH2 domain or C-SH2 domains, or mutation of tyrosine 542, in vitro and inhibit ligand-stimulated phospho-Erk activation in severely abrogated the transforming ability of the E76K mu- cells, in contrast to the gain-of-function mutations observed in tant,76,77 suggesting that both the enzymatic function as well as the NS.60,62 However, the Shp2 crystal structure predicts that the adapter function of Shp2 substantially contribute to the transform- Y279C and T468M mutant proteins reside preferentially in the ing ability of the Shp2 mutants. open conformation, suggesting that these mutant proteins may Approximately 50% of mice reconstituted with hematopoietic exert defective signaling in vivo due to aberrant adapter function in progenitors transduced with PTPN11 mutants E76K or D61Y assembling multiprotein signaling complexes or due to competition succumbed to malignant hematologic disease by 7 months after with WT Shp2 for substrates. 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 Functional and signal transduction progressive, lethal form of MPD is in contrast to the later-onset, alternations induced by PTPN11 mutations nonlethal, chronic myelomonocytic hyperplasia observed in a mouse model bearing the common NS germ line PTPN11 mutation, JMML is a rare clonal MPD of children younger than 5 years of age D61G.78 This variable transforming ability of the different PTPN11 and is characterized clinically by hepatosplenomegaly, increased mutants in part rationalizes the unpredictable clinical course of circulating monocytes and erythroblasts, and increased production JMML in patients with NS bearing germ line PTPN11 mutations, of fetal hemoglobin (HbF), implying a regression to fetallike which spans from mild disease ending in spontaneous remission to hematopoiesis.63 In vitro, hematopoietic progenitors from patients progressive cases ending in death.40 with JMML demonstrate hypersensitivity to GM-CSF.64 Hyperacti- One peculiar observation is that the incidence of somatic vation of Ras is implicated in the pathogenesis of JMML based on PTPN11 mutations is higher in JMML compared with acute the identification of activating NRAS and KRAS mutations65,66 and leukemias and solid tumors. A contributing factor to this phenom- loss-of-heterozygosity of NF1 in patient samples (Figure 3).67 enon may be the cell population targeted by PTPN11 mutations Well-studied molecular mechanisms leading to JMML in humans leading to JMML. A recent study examining a GATA1 mutation with NF1 and in animal models bearing Nf1 loss-of-function or found in individuals with Down syndrome and transient MPD or activating Kras mutations are instructive when considering the acute megakaryoblastic leukemia revealed a novel embryonic potential molecular aberrations induced by activating PTPN11 progenitor population targeted by this mutation.79 Similarly, fetal From www.bloodjournal.org by guest on July 4, 2016. For personal use only.

866 CHAN and FENG BLOOD, 1 FEBRUARY 2007 ⅐ VOLUME 109, NUMBER 3 myeloid progenitors may be exceptionally sensitive to the effects of scope of oncogenes, but also refresh our views on the critical activating PTPN11 mutations compared with those of adult my- difference between proto-oncogenes and oncogenes mediating eloid progenitors. Interaction with a second, cooperating mutation either physiologic regulation or pathologic dysregulation in normal or modifier loci may be required for clonal outgrowth progressing cells and malignant cells, respectively. One important functional to frank JMML, while the absence of these functional genetic consequence of activating PTPN11 or KRAS mutations or loss-of- interactions may allow for the spontaneous remission of JMML, as function NF1 mutations is Ras hyperactivation; therefore, Ras observed in some patients with NS with germ line PTPN11 effectors, such as Mek and PI3K, are rational targets for novel mutations.40 Although speculative, this hypothesis is consistent therapeutics in JMML. Indeed, in vitro treatment of hematopoietic with the finding that murine transplantation of PTPN11 mutant– progenitors with the Mek inhibitor, UO126, or with rapamycin, an bearing cells produced robust MPD on the Balb/c background and inhibitor of the PI3K-mTOR pathway, reduces the transforming only subtle abnormalities on the C57Bl/6 background.76,77 ability of PTPN11 mutant E76K.76 The current challenge entails Although PTPN11 mutations are found only rarely in adult building on this broad fund of knowledge to define novel molecular leukemias,80-82 recent studies demonstrate elevated Shp2 expres- targets with the objective of developing improved therapeutics for sion in primary leukemia cell specimens from multiple adult acute pediatric and adult myeloid leukemias. leukemias, compared with Shp2 levels in bone marrow mono- nuclear cells from healthy controls.82 Upon terminal differentia- tion, Shp2 expression diminished, suggesting that persistently Acknowledgments elevated Shp2 expression may lead to perturbations in hematopoi- etic cell differentiation.82 Consistently, overexpression of WT Shp2 The authors wish to acknowledge the tenacious genotyping work of inhibited macrophage progenitor differentiation in response to multiple investigators reviewed by Tartaglia and Gelb.39 Addition- macrophage colony-stimulating factor (M-CSF) based on F4/80 ally, the authors thank Dr Mignon Loh for helpful discussion in the expression,75 suggesting that excessive Shp2 may inhibit or delay presentation of the genotyping data. Work in authors’ laboratories the maturation of myeloid progenitors, contributing to was supported by the March of Dimes (Basil O’Connor Starter leukemogenesis. 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 Contribution: R.J.C. and G.-S.F. wrote and revised the paper. proto-oncogene that encodes a PTP. Strikingly, a similar molecular Conflict-of-interest disclosure: The authors declare no compet- mechanism is employed in oncogenic activation of an intracellular ing financial interests. PTK (c-Src) or a PTP (Shp2), which involves disruption of an Correspondence: Gen-Sheng Feng, Burnham Institute for Medi- autoinhibitory intramolecular interaction leading to constitutive cal Research, 10901 N Torrey Pines Rd, La Jolla, CA 92037; activation. Thus, the studies on mutant Shp2 not only expand the e-mail: [email protected]. References

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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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