The Experts below are selected from a list of 14238 Experts worldwide ranked by ideXlab platform
Tsutomu Ogata - One of the best experts on this subject based on the ideXlab platform.
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PTPN11 mutations and genotype-phenotype correlations in Noonan and LEOPARD syndromes.
Pediatric endocrinology reviews, 2005Co-Authors: Tsutomu Ogata, Rie YoshidaAbstract:: This review summarizes PTPN11 (protein-tyrosine phosphatase, nonreceptor type 11) mutations and genotype-phenotype correlations in Noonan syndrome (NS) and LEOPARD syndrome (LS). PTPN11 mutations have been identified in approximately 40% of NS patients and in >80% of LS patients. Since the vast majority of mutations reside in and around the broad intramolecular interaction surface between the N-SH2 and PTP domains of the PTPN11 protein, they have been suggested to affect the intramolecular N-SH2/PTP binding in the absence of a phosphopeptide, leading to excessive phosphatase activities. The type of mutations is diverse in NS and limited in LS, and is almost mutually exclusive between NS and LS. Clinical assessment in NS patients implies that cardiovascular anomalies and hematologic abnormalities are predominant in mutation positive patients, hypertrophic cardiomyopathy is predominant in mutation negative patients, and growth deficiency, mental retardation, and minor somatic anomalies are similar between the two groups of patients. Phenotypic evaluation in LS patients suggests that a hypertrophic cardiomyopathy rather than an electrocardiographic conduction abnormality is characteristic of PTPN11 mutation positive patients.
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a 3 bp deletion mutation of PTPN11 in an infant with severe noonan syndrome including hydrops fetalis and juvenile myelomonocytic leukemia
American Journal of Medical Genetics Part A, 2004Co-Authors: Rie Yoshida, Masafumi Miyata, Toshiro Nagai, Toshio Yamazaki, Tsutomu OgataAbstract:A de novo 3-bp deletion (179–181delGTG) was identified at exon 3 of the PTPN11 gene in a female infant with severe Noonan phenotype including hydrops fetalis and juvenile myelomonocytic leukemia. Since the 3-bp deletion is predicted to result in loss of the 60th glycine in the N-SH2 domain that is directly involved in the intramolecular interaction between the N-SH2 and the PTP domains of the PTPN11 protein, this mutation would disrupt the N-SH2/PTP binding in the absence of a phosphopeptide, leading to an excessive phosphatase activity. The results expand the spectrum of PTPN11 mutations in Noonan syndrome (NS), and suggest that a PTPN11 mutation leads to a wide range of clinical features of Noonan syndrome. © 2004 Wiley-Liss, Inc.
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A 3-bp deletion mutation of PTPN11 in an infant with severe Noonan syndrome including hydrops fetalis and juvenile myelomonocytic leukemia.
American Journal of Medical Genetics Part A, 2004Co-Authors: Rie Yoshida, Masafumi Miyata, Toshiro Nagai, Toshio Yamazaki, Tsutomu OgataAbstract:A de novo 3-bp deletion (179-181delGTG) was identified at exon 3 of the PTPN11 gene in a female infant with severe Noonan phenotype including hydrops fetalis and juvenile myelomonocytic leukemia. Since the 3-bp deletion is predicted to result in loss of the 60th glycine in the N-SH2 domain that is directly involved in the intramolecular interaction between the N-SH2 and the PTP domains of the PTPN11 protein, this mutation would disrupt the N-SH2/PTP binding in the absence of a phosphopeptide, leading to an excessive phosphatase activity. The results expand the spectrum of PTPN11 mutations in Noonan syndrome (NS), and suggest that a PTPN11 mutation leads to a wide range of clinical features of Noonan syndrome.
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PTPN11 protein tyrosine phosphatase nonreceptor type 11 mutations in seven japanese patients with noonan syndrome
The Journal of Clinical Endocrinology and Metabolism, 2002Co-Authors: Kenjiro Kosaki, Toshiro Nagai, T Suzuki, Koji Muroya, Tomonobu Hasegawa, Seiji Sato, Nobutake Matsuo, Rika Kosaki, Yukihiro Hasegawa, Tsutomu OgataAbstract:Noonan syndrome is an autosomal dominant disorder defined by short stature, delayed puberty, and characteristic dysmorphic features. Tartaglia et al. (Nature Genetics, 29:465-468) have recently shown that gain-of-function mutations in the gene PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) cause Noonan syndrome in roughly half of patients that they examined. To further explore the relevance of PTPN11 mutations to the pathogenesis of Noonan syndrome, we analyzed the PTPN11 gene in 21 Japanese patients. Mutation analysis of the 15 coding exons and their flanking introns by denaturing HPLC and direct sequencing revealed six different heterozygous missense mutations (Asp61Gly, Tyr63Cys, Ala72Ser, Thr73Ile, Phe285Ser, and Asn308Asp) in seven cases (six sporadic and one familial). The mutations clustered either in the N-Src homology 2 domain or in the protein-tyrosine phosphatase domain. The clinical features of the mutation-positive and mutation-negative patients were comparable. The results provide further support to the notion that PTPN11 mutations are responsible for the development of Noonan syndrome in a substantial fraction of patients and that relatively infrequent features of Noonan syndrome, such as sensory deafness and bleeding diathesis, can also result from mutations of PTPN11.
Marco Tartaglia - One of the best experts on this subject based on the ideXlab platform.
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structural determinants of phosphopeptide binding to the n terminal src homology 2 domain of the shp2 phosphatase
Journal of Chemical Information and Modeling, 2020Co-Authors: Massimiliano Anselmi, Marco Tartaglia, Paolo Calligari, Jochen S Hub, Gianfranco Bocchinfuso, Lorenzo StellaAbstract:SH2 domain-containing tyrosine phosphatase 2 (SHP2), encoded by PTPN11, plays a fundamental role in the modulation of several signaling pathways. Germline and somatic mutations in PTPN11 are associ...
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phosphatase defective leopard syndrome mutations in PTPN11 gene have gain of function effects during drosophila development
Human Molecular Genetics, 2009Co-Authors: Kimihiko Oishi, Marco Tartaglia, Hui Zhang, William J Gault, Cindy J Wang, Huiwen Ying, Tabassum Rahman, Natalie Pica, Marek Mlodzik, Bruce D. GelbAbstract:Missense mutations in the PTPN11 gene, which encodes the protein tyrosine phosphatase SHP-2, cause clinically similar but distinctive disorders, LEOPARD (LS) and Noonan (NS) syndromes. The LS is an autosomal dominant disorder with pleomorphic developmental abnormalities including lentigines, cardiac defects, short stature and deafness. Biochemical analyses indicated that LS alleles engender loss-of-function (LOF) effects, while NS mutations result in gain-of-function (GOF). These biochemical findings lead to an enigma that how PTPN11 mutations with opposite effects on function result in disorders that are so similar. To study the developmental effects of the commonest LS PTPN11 alleles (Y279C and T468M), we generated LS transgenic fruitflies using corkscrew (csw), the Drosophila orthologue of PTPN11. Ubiquitous expression of the LS csw mutant alleles resulted in ectopic wing veins and, for the Y279C allele, rough eyes with increased R7 photoreceptor numbers. These were GOF phenotypes mediated by increased RAS/MAPK signaling and requiring the LS mutant’s residual phosphatase activity. Our findings provide the first evidence that LS mutant alleles have GOF developmental effects despite reduced phosphatase activity, providing a rationale for how PTPN11 mutations with GOF and LOF produce similar but distinctive syndromes.
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Genomic duplication of PTPN11 is an uncommon cause of Noonan syndrome.
American journal of medical genetics. Part A, 2009Co-Authors: John M Graham, Marco Tartaglia, Claudio Carta, Nancy Kramer, Bassem A Bejjani, Christian T Thiel, Giovanni Neri, Martin ZenkerAbstract:Noonan syndrome (NS) is a genetically heterogeneous disorder caused most commonly by activating mutations in PTPN11. We report a patient with hypotonia, developmental delay and clinical features suggestive of NS. High-resolution chromosome analysis was normal, and sequence analyses of PTPN11, SOS1, KRAS, BRAF, RAF1, MEK, and MEK2 were also normal. Array CGH revealed a single copy gain of 9 BAC clones at 12q24.11q24.21 (8.98 Mb in size), which encompassed the PTPN11 locus at 12q24.13 and was confirmed by FISH analysis. Shchelochkov et al. [Shchelochkov et al. (2008); Am J Med Genet Part A 146A:1042-1048] reported a similar case and speculated that such duplications might account for 15-30% of NS cases with no detectable mutation in NS genes. We screened more than 250 NS cases without mutation in known NS disease-causing genes by quantitative PCR, and none of these studies produced results in the duplicated range. We also explored the possibility that de novo changes affecting the untranslated region (UTR) of the PTPN11 transcript might represent an alternative event involved in SHP2 enhanced expression. DHPLC analysis and direct sequencing of the entire 3' UTR in 36 NS patients without mutation in known genes did not show any disease-associated variant. These findings indicate that duplications of PTPN11 represent an uncommon cause of NS, and functionally relevant variations within the 3'UTR of the gene do not appear to play a major role in NS. However, recurrent observations of NS in individuals with duplications involving the PTPN11 locus suggest that increased dosage of SHP2 may have dysregulating effects on intracellular signaling.
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Somatic PTPN11 mutations in childhood acute myeloid leukaemia
British journal of haematology, 2005Co-Authors: Marco Tartaglia, Simone Martinelli, Giovanni Cazzaniga, Ivano Iavarone, Monica Spinelli, Claudio Carta, Emanuela Giarin, Valentina Petrangeli, Riccardo Masetti, Maurizio AricoAbstract:Somatic mutations in PTPN11, the gene encoding the transducer SHP-2, have emerged as a novel class of lesions that upregulate RAS signalling and contribute to leukaemogenesis. In a recent study of 69 children and adolescents with de novo acute myeloid leukaemia (AML), we documented a non-random distribution of PTPN11 mutations among French-American-British (FAB) subtypes. Lesions were restricted to FAB-M5 cases, where they were relatively common (four of 12 cases). Here, we report on the results of a molecular screening performed on 181 additional unselected patients, enrolled in participating institutions of the Associazione Italiana Ematologia Oncologia Pediatrica-AML Study Group, to provide a more accurate picture of the prevalence, spectrum and distribution of PTPN11 mutations in childhood AML and to investigate their clinical relevance. We concluded that PTPN11 defects do not represent a frequent event in this heterogeneous group of malignancies (4.4%), although they recur in a considerable percentage of patients with FAB-M5 (18%). PTPN11 lesions rarely occur in other subtypes. Within the FAB-M5 group no clear association of PTPN11 mutations with any clinical variable was evident. Nearly two third of the patients with this subtype were found to harbour an activating mutation in PTPN11, NRAS, KRAS2 or FLT3.
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genetic evidence for lineage related and differentiation stage related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia
Blood, 2004Co-Authors: Marco Tartaglia, Simone Martinelli, Giovanni Cazzaniga, Viviana Cordeddu, Ivano Iavarone, Monica Spinelli, Chiara Palmi, Claudio Carta, Andrea Pession, Maurizio AricoAbstract:SHP-2 is a protein tyrosine phosphatase functioning as signal transducer downstream to growth factor and cytokine receptors. SHP-2 is required during development, and germline mutations in PTPN11, the gene encoding SHP-2, cause Noonan syndrome. SHP-2 plays a crucial role in hematopoietic cell development. We recently demonstrated that somatic PTPN11 mutations are the most frequent lesion in juvenile myelomonocytic leukemia and are observed in a smaller percentage of children with other myeloid malignancies. Here, we report that PTPN11 lesions occur in childhood acute lymphoblastic leukemia (ALL). Mutations were observed in 23 of 317 B-cell precursor ALL cases, but not among 44 children with T-lineage ALL. In the former, lesions prevalently occurred in TEL-AML1(-) cases with CD19(+)/CD10(+)/cyIgM(-) immunophenotype. PTPN11, NRAS, and KRAS2 mutations were largely mutually exclusive and accounted for one third of common ALL cases. We also show that, among 69 children with acute myeloid leukemia, PTPN11 mutations occurred in 4 of 12 cases with acute monocytic leukemia (FAB-M5). Leukemia-associated PTPN11 mutations were missense and were predicted to result in SHP-2 gain-of-function. Our findings provide evidence for a wider role of PTPN11 lesions in leukemogenesis, but also suggest a lineage-related and differentiation stage-related contribution of these lesions to clonal expansion.
Benjamin G Neel - One of the best experts on this subject based on the ideXlab platform.
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Role of PTPN11 (SHP2) in Cancer
Protein Tyrosine Phosphatases in Cancer, 2016Co-Authors: Gordon Chan, Benjamin G NeelAbstract:Src homology-2 domain-containing phosphatase 2 (SHP2), encoded by the PTPN11 gene, is a highly conserved, non-transmembrane protein-tyrosine phosphatase (PTP), found in all metazoans. The molecular details of SHP2 regulation by phosphotyrosyl (pTyr) peptide ligand binding are well-understood, and knowledge of these details is critical to understanding SHP2 function in health and disease. Studies using mice with gain- or loss-of-function alleles of PTPN11 have provided much detail about the physiological functions and signaling pathways regulated by SHP2 at the cellular and whole organism levels. Germline mutations in PTPN11 cause Noonan syndrome, Noonan syndrome with multiple lentigines (previously, LEOPARD syndrome), as well as the cartilage tumor syndrome, metachondromatosis. Somatic PTPN11 mutations occur in several types of hematologic malignancy, most notably juvenile myelomonocytic leukemia and, more rarely, in neuroblastoma and other solid tumors. PTPN11 is crucial for transformation initiated by mutant receptor-tyrosine kinases (RTKs) and is an important effector of H. pylori virulence. However, the direct target(s) of SHP2 responsible for its physiological and pathological effects remain controversial and their identification remains a major goal for the future research.
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gain of function mutations of PTPN11 shp2 cause aberrant mitosis and increase susceptibility to dna damage induced malignancies
Proceedings of the National Academy of Sciences of the United States of America, 2016Co-Authors: Xia Liu, Hong Zheng, Siying Wang, Wentian Yang, Howard J Meyerson, Benjamin G NeelAbstract:Gain-of-function (GOF) mutations of protein tyrosine phosphatase nonreceptor type 11 PTPN11 (Shp2), a protein tyrosine phosphatase implicated in multiple cell signaling pathways, are associated with childhood leukemias and solid tumors. The underlying mechanisms are not fully understood. Here, we report that PTPN11 GOF mutations disturb mitosis and cytokinesis, causing chromosomal instability and greatly increased susceptibility to DNA damage-induced malignancies. We find that Shp2 is distributed to the kinetochore, centrosome, spindle midzone, and midbody, all of which are known to play critical roles in chromosome segregation and cytokinesis. Mouse embryonic fibroblasts with PTPN11 GOF mutations show a compromised mitotic checkpoint. Centrosome amplification and aberrant mitosis with misaligned or lagging chromosomes are significantly increased in PTPN11-mutated mouse and patient cells. Abnormal cytokinesis is also markedly increased in these cells. Further mechanistic analyses reveal that GOF mutant Shp2 hyperactivates the Polo-like kinase 1 (Plk1) kinase by enhancing c-Src kinase-mediated tyrosine phosphorylation of Plk1. This study provides novel insights into the tumorigenesis associated with PTPN11 GOF mutations and cautions that DNA-damaging treatments in Noonan syndrome patients with germ-line PTPN11 GOF mutations could increase the risk of therapy-induced malignancies.
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Leukemogenic PTPN11 Allele Causes Defective Erythropoiesis in Mice
PloS one, 2014Co-Authors: Tatiana Usenko, Gordon Chan, Emina Torlakovic, Ursula Klingmüller, Benjamin G NeelAbstract:Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2), encoded by PTPN11, regulates signaling networks and cell fate in many tissues. Expression of oncogenic PTPN11 in the hematopoietic compartment causes myeloproliferative neoplasm (MPN) in humans and mice. However, the stage-specific effect(s) of mutant PTPN11 on erythroid development have remained unknown. We found that expression of an activated, leukemogenic PTPN11 allele, PTPN11D61Y, specifically in the erythroid lineage causes dyserythropoiesis in mice. PTPN11D61Y progenitors produce excess cKIT+CD71+Ter119− cells and aberrant numbers of cKITl°CD71+ erythroblasts. Mutant erythroblasts show elevated activation of ERK, AKT and STAT3 in response to EPO stimulation, and MEK inhibitor treatment blocks PTPN11D61Y-evoked erythroid hyperproliferation in vitro. Thus, the expression of oncogenic PTPN11 causes dyserythropoiesis in a cell-autonomous manner in vivo.
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structural insights into noonan leopard syndrome related mutants of protein tyrosine phosphatase shp2 PTPN11
BMC Structural Biology, 2014Co-Authors: V Romanov, Maxim Ruzanov, Benjamin G Neel, Nickolay Y Chirgadze, Kevin P Battaile, Ashley Hutchinson, Xiaonan WangAbstract:Background The ubiquitous non-receptor protein tyrosine phosphatase SHP2 (encoded by PTPN11) plays a key role in RAS/ERK signaling downstream of most, if not all growth factors, cytokines and integrins, although its major substrates remain controversial. Mutations in PTPN11 lead to several distinct human diseases. Germ-line PTPN11 mutations cause about 50% of Noonan Syndrome (NS), which is among the most common autosomal dominant disorders. LEOPARD Syndrome (LS) is an acronym for its major syndromic manifestations: multiple Lentigines, Electrocardiographic abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormalities of genitalia, Retardation of growth, and sensorineural Deafness. Frequently, LS patients have hypertrophic cardiomyopathy, and they might also have an increased risk of neuroblastoma (NS) and acute myeloid leukemia (AML). Consistent with the distinct pathogenesis of NS and LS, different types of PTPN11 mutations cause these disorders.
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Structural insights into Noonan/LEOPARD syndrome-related mutants of protein-tyrosine phosphatase SHP2 ( PTPN11 )
BMC Structural Biology, 2014Co-Authors: Xiaonan Wang, V Romanov, Maxim Ruzanov, Benjamin G Neel, Kevin P Battaile, Ashley Hutchinson, Nickolay Y ChirgadzeAbstract:Background The ubiquitous non-receptor protein tyrosine phosphatase SHP2 (encoded by PTPN11) plays a key role in RAS/ERK signaling downstream of most, if not all growth factors, cytokines and integrins, although its major substrates remain controversial. Mutations in PTPN11 lead to several distinct human diseases. Germ-line PTPN11 mutations cause about 50% of Noonan Syndrome (NS), which is among the most common autosomal dominant disorders. LEOPARD Syndrome (LS) is an acronym for its major syndromic manifestations: multiple Lentigines, Electrocardiographic abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormalities of genitalia, Retardation of growth, and sensorineural Deafness. Frequently, LS patients have hypertrophic cardiomyopathy, and they might also have an increased risk of neuroblastoma (NS) and acute myeloid leukemia (AML). Consistent with the distinct pathogenesis of NS and LS, different types of PTPN11 mutations cause these disorders.
Kristen S Hill - One of the best experts on this subject based on the ideXlab platform.
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Abstract PR13: PTPN11 plays oncogenic roles and is a therapeutic target for BRAF wild-type melanomas
Cancer Research, 2019Co-Authors: Kristen S Hill, Evan R Roberts, Jamie K Teer, Jane L Messina, Xue Wang, John M. Koomen, Young-chul Kim, Charles E. Chalfant, Minjung KimAbstract:Melanoma is one of the most highly mutated cancer types, harboring numerous alterations with unknown significance. To identify functional drivers of melanoma, we searched for cross-species conserved mutations utilizing a mouse melanoma model driven by loss of PTEN and CDKN2A, and identified mutations in Kras, Erbb3, and PTPN11. PTPN11 encodes the SHP2 protein tyrosine phosphatase (PTP) that activates the RAS/RAF/MAPK pathway. Although PTPN11 is an oncogene in leukemia, lung, and breast cancers, its roles in melanoma are not clear. In this study, we found that PTPN11 is frequently activated in human melanoma specimens and cell lines and is required for full RAS/RAF/MAPK signaling activation in BRAF wild-type (either NRAS mutant or wild-type) melanoma cells. PTPN11 played oncogenic roles in melanoma by driving anchorage-independent colony formation and tumor growth. In Pten and Cdkn2a null mice, tet-inducible and melanocyte-specific PTPN11E76K expression significantly enhanced melanoma tumorigenesis. Melanoma cells derived from this mouse model showed doxycycline-dependent tumor growth in nude mice. Silencing PTPN11E76K expression by doxycycline withdrawal caused regression of established tumors by induction of apoptosis and senescence and suppression of proliferation. Moreover, the PTPN11 inhibitor (SHP099) also caused regression of NRASQ61K-mutant melanoma. Using a quantitative tyrosine phospho-proteomics approach, we identified GSK3α/β as one of the key substrates that were differentially tyrosine-phosphorylated in these experiments modulating PTPN11. This study demonstrates that PTPN11 plays oncogenic roles in melanoma and regulates RAS and GSK3α/β signaling pathways. This study also identifies PTPN11 as a novel and actionable therapeutic target for BRAF wild-type melanoma. This abstract is also being presented as Poster A14. Citation Format: Kristen S. Hill, Evan R. Roberts, Xue Wang, John M. Koomen, Jane L. Messina, Jamie K. Teer, Youngchul Kim, Jie Wu, Charles E. Chalfant, Minjung Kim. PTPN11 plays oncogenic roles and is a therapeutic target for BRAF wild-type melanomas [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr PR13.
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PTPN11 Plays Oncogenic Roles and Is a Therapeutic Target for BRAF Wild-Type Melanomas
Molecular cancer research : MCR, 2018Co-Authors: Kristen S Hill, Evan R Roberts, Ellen Marin, Xue Wang, Taeeun D. Park, Sorany Son, Yuan Ren, Bin Fang, Sean Yoder, Sungjune KimAbstract:Melanoma is one of the most highly mutated cancer types. To identify functional drivers of melanoma, we searched for cross-species conserved mutations utilizing a mouse melanoma model driven by loss of PTEN and CDKN2A, and identified mutations in Kras, Erbb3, and PTPN11. PTPN11 encodes the SHP2 protein tyrosine phosphatase that activates the RAS/RAF/MAPK pathway. Although PTPN11 is an oncogene in leukemia, lung, and breast cancers, its roles in melanoma are not clear. In this study, we found that PTPN11 is frequently activated in human melanoma specimens and cell lines and is required for full RAS/RAF/MAPK signaling activation in BRAF wild-type (either NRAS mutant or wild-type) melanoma cells. PTPN11 played oncogenic roles in melanoma by driving anchorage-independent colony formation and tumor growth. In Pten- and Cdkn2a-null mice, tet-inducible and melanocyte-specific PTPN11E76K expression significantly enhanced melanoma tumorigenesis. Melanoma cells derived from this mouse model showed doxycycline-dependent tumor growth in nude mice. Silencing PTPN11E76K expression by doxycycline withdrawal caused regression of established tumors by induction of apoptosis and senescence, and suppression of proliferation. Moreover, the PTPN11 inhibitor (SHP099) also caused regression of NRASQ61K -mutant melanoma. Using a quantitative tyrosine phosphoproteomics approach, we identified GSK3α/β as one of the key substrates that were differentially tyrosine-phosphorylated in these experiments modulating PTPN11. This study demonstrates that PTPN11 plays oncogenic roles in melanoma and regulates RAS and GSK3β signaling pathways. IMPLICATIONS: This study identifies PTPN11 as an oncogenic driver and a novel and actionable therapeutic target for BRAF wild-type melanoma.
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Abstract 2387: The oncogenic role and therapeutic potential of PTPN11 in melanoma
Molecular and Cellular Biology Genetics, 2018Co-Authors: Kristen S Hill, Evan R Roberts, Ellen Marin, Jamie K Teer, Jane L Messina, Xue Wang, Minjung KimAbstract:The RAS/RAF/MEK/ERK signaling pathway, which is intricately regulated by multiple proteins including PTPN11 (Tyrosine-Protein Phosphatase Non-Receptor Type 11, encoding SHP2), is frequently activated in melanoma. Although implicated as an oncogene in multiple cancer types, the oncogenic role of PTPN11 has not been established in melanoma. Recently, we preformed whole exome sequencing on tumors generated by a mouse model driven by loss of PTEN and CDKN2A (INK4A/ARF) and identified several conserved cross-species orthologous mutations in Kras, Erbb3, and PTPN11. In this study, we addressed the functional roles of PTPN11 in melanoma tumorigenesis and tumor maintenance; as well as, PTPN119s effect on the RAS/RAF/MEK/ERK signaling pathway and its activation status in human melanoma. PTPN11 can be activated by receptor tyrosine kinases (RTKs) or by point mutations. We observed activating phosphorylation on Tyr 542 of PTPN11 in 40% (n=15/38) of melanoma specimens and the majority of human melanoma cell lines (n=14), supporting frequent activation of PTPN11 in human melanoma even though the mutation rate is low (1~3%). PTPN11 knock-down suppressed ERK activation in NRAS mutant and BRAF/NRAS wild-type melanoma cells, but not in BRAF mutant cells. Moreover, we have shown that expression of active PTPN11E76K mutant drives soft-agar colony growth in vitro, tumor growth in nude mice, RAS/RAF/MEK/ERK activation, and resistance to MEK inhibition. Alternatively, knock-down of PTPN11 reduces colony growth and ERK activation. We generated a tet-inducible, melanocyte-specific, PTPN11E76K transgenic mouse model in a PTEN and CDKN2A null background and observed melanoma formation. Implantation of melanoma cells derived from this model showed doxycycline dependent tumor growth in nude mice. Doxycycline withdrawal and subsequent extinction of PTPN11E76K caused regression of established tumors, supporting the tumor maintenance role of PTPN11. Subsequently, tumor tissue from this model underwent phosphor-tyrosine proteomic analysis to identify downstream effectors of PTPN119s protein tyrosine phosphatase activity. The proteins identified in this analysis are currently being confirmed. These data support the oncogenic roles of PTPN11 in melanoma by regulating RAS/RAF/MAPK pathway activation and the value of PTPN11 as a novel and actionable therapeutic target. Citation Format: Kristen Suzanne Hill, Evan Roberts, Ellen Marin, Xue Wang, Jamie Teer, Jane Messina, Jerry Wu, Minjung Kim. The oncogenic role and therapeutic potential of PTPN11 in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2387.
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abstract a04 cross species oncogenomics approach identifies PTPN11 as an oncogene and potential therapeutic target in melanoma
Cancer Research, 2018Co-Authors: Kristen S Hill, Evan R Roberts, Ellen Marin, Jamie K Teer, Jane L Messina, Xue Wang, Jie WuAbstract:Melanoma is a deadly disease carrying many genetic mutations. A major challenge to the development of effective targeted therapies in melanoma is the identification of true “driver” mutations among numerous “passenger” alterations. Several previous studies support using cross-species comparative oncogenomic approaches for cancer gene discovery. Specifically, it has been shown that mice and humans share several genetic events in the development of cancer and that these events that are conserved across different species may point to functionally important and evolutionary conserved alterations targeting “driver” genes. Recently, we analyzed melanoma genomes from a mouse model driven by the loss of PTEN and CDKN2A (INK4A/ARF), commonly observed alterations in human melanoma patients, by whole-exome sequencing. This study identified several conserved cross-species orthologous mutations in Kras , Erbb3 , and PTPN11 . In this study, we addressed the functional roles of PTPN11 in melanoma tumorigenesis and tumor maintenance, its effect on RAS/RAF/MEK/ERK signaling pathway, and its activation status in human melanoma. Melanoma displays frequent activation of the RAS/RAF/MEK/ERK signaling pathway, which is intricately regulated by multiple proteins including PTPN11 (Tyrosine-Protein Phosphatase Non-Receptor Type 11, encoding SHP2). Although implicated as an oncogene in multiple cancer types, the oncogenic role of PTPN11 has not been fully established in melanoma. PTPN11 can be activated by receptor tyrosine kinases (RTKs) and/or by point mutations. Although the mutation rate is low (1~3%), we observed activating phosphorylation on Tyr 542 of PTPN11 in 40% (n=15/38) of melanoma specimens and the majority of human melanoma cell lines (n=14), indicating the potential frequent activation of PTPN11 in human melanoma. PTPN11 knock-down suppressed ERK activation in NRAS mutant (WM1361A, 1366, 1346) and BRAF/NRAS wt (WM3211, MeWo, CHL1) melanoma cells, but not in BRAF mutant (1205Lu, IGR1, 983C) cells. Moreover, we have shown that the expression of active PTPN11 E76K mutant drives soft-agar colony growth in vitro, tumor growth in nude mice, RAS/RAF/MEK/ERK activation, and resistance to MEK inhibition, whereas knock-down of PTPN11 reduces colony growth and ERK activation. We generated a tet -inducible, melanocyte-specific, PTPN11 E76K transgenic mouse model in a Pten and Cdkn2a null background and observed melanoma formation. Implantation of melanoma cells derived from this model showed doxycycline-dependent tumor growth in nude mice; additionally, withdrawal of doxycycline and subsequent extinction of PTPN11 E76K caused regression of established tumors, supporting a tumor-maintenance role of PTPN11. These data support the oncogenic roles of PTPN11 in melanoma by regulating RAS/RAF/MAPK pathway activation and the value of PTPN11 as a novel and actionable therapeutic target. Citation Format: Kristen S. Hill, Xue Wang, Evan R. Roberts, Ellen M. Marin, Jamie K. Teer, Youngchul Kim, Jane Messina, Jie Wu, Minjung Kim. Cross-species oncogenomics approach identifies PTPN11 as an oncogene and potential therapeutic target in melanoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A04.
Rie Yoshida - One of the best experts on this subject based on the ideXlab platform.
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PTPN11 mutations and genotype-phenotype correlations in Noonan and LEOPARD syndromes.
Pediatric endocrinology reviews, 2005Co-Authors: Tsutomu Ogata, Rie YoshidaAbstract:: This review summarizes PTPN11 (protein-tyrosine phosphatase, nonreceptor type 11) mutations and genotype-phenotype correlations in Noonan syndrome (NS) and LEOPARD syndrome (LS). PTPN11 mutations have been identified in approximately 40% of NS patients and in >80% of LS patients. Since the vast majority of mutations reside in and around the broad intramolecular interaction surface between the N-SH2 and PTP domains of the PTPN11 protein, they have been suggested to affect the intramolecular N-SH2/PTP binding in the absence of a phosphopeptide, leading to excessive phosphatase activities. The type of mutations is diverse in NS and limited in LS, and is almost mutually exclusive between NS and LS. Clinical assessment in NS patients implies that cardiovascular anomalies and hematologic abnormalities are predominant in mutation positive patients, hypertrophic cardiomyopathy is predominant in mutation negative patients, and growth deficiency, mental retardation, and minor somatic anomalies are similar between the two groups of patients. Phenotypic evaluation in LS patients suggests that a hypertrophic cardiomyopathy rather than an electrocardiographic conduction abnormality is characteristic of PTPN11 mutation positive patients.
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a 3 bp deletion mutation of PTPN11 in an infant with severe noonan syndrome including hydrops fetalis and juvenile myelomonocytic leukemia
American Journal of Medical Genetics Part A, 2004Co-Authors: Rie Yoshida, Masafumi Miyata, Toshiro Nagai, Toshio Yamazaki, Tsutomu OgataAbstract:A de novo 3-bp deletion (179–181delGTG) was identified at exon 3 of the PTPN11 gene in a female infant with severe Noonan phenotype including hydrops fetalis and juvenile myelomonocytic leukemia. Since the 3-bp deletion is predicted to result in loss of the 60th glycine in the N-SH2 domain that is directly involved in the intramolecular interaction between the N-SH2 and the PTP domains of the PTPN11 protein, this mutation would disrupt the N-SH2/PTP binding in the absence of a phosphopeptide, leading to an excessive phosphatase activity. The results expand the spectrum of PTPN11 mutations in Noonan syndrome (NS), and suggest that a PTPN11 mutation leads to a wide range of clinical features of Noonan syndrome. © 2004 Wiley-Liss, Inc.
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A 3-bp deletion mutation of PTPN11 in an infant with severe Noonan syndrome including hydrops fetalis and juvenile myelomonocytic leukemia.
American Journal of Medical Genetics Part A, 2004Co-Authors: Rie Yoshida, Masafumi Miyata, Toshiro Nagai, Toshio Yamazaki, Tsutomu OgataAbstract:A de novo 3-bp deletion (179-181delGTG) was identified at exon 3 of the PTPN11 gene in a female infant with severe Noonan phenotype including hydrops fetalis and juvenile myelomonocytic leukemia. Since the 3-bp deletion is predicted to result in loss of the 60th glycine in the N-SH2 domain that is directly involved in the intramolecular interaction between the N-SH2 and the PTP domains of the PTPN11 protein, this mutation would disrupt the N-SH2/PTP binding in the absence of a phosphopeptide, leading to an excessive phosphatase activity. The results expand the spectrum of PTPN11 mutations in Noonan syndrome (NS), and suggest that a PTPN11 mutation leads to a wide range of clinical features of Noonan syndrome.
