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Kontaridis, Maria

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Kontaridis

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Maria

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Kontaridis, Maria
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    The third international meeting on genetic disorders in the RAS/MAPK pathway: Towards a therapeutic approach
    (Wiley-Blackwell, 2015) Korf, Bruce; Ahmadian, Reza; Allanson, Judith; Aoki, Yoko; Bakker, Annette; Wright, Emma Burkitt; Denger, Brian; Elgersma, Ype; Gelb, Bruce D.; Gripp, Karen W.; Kerr, Bronwyn; Kontaridis, Maria; Lazaro, Conxi; Linardic, Corinne; Lozano, Reymundo; MacRae, Calum; Messiaen, Ludwine; Mulero-Navarro, Sonia; Neel, Benjamin; Plotkin, Scott; Rauen, Katherine A.; Roberts, Amy; Silva, Alcino J.; Sittampalam, Sitta G.; Zhang, Chao; Schoyer, Lisa
    "The Third International Meeting on Genetic Disorders in the RAS/MAPK Pathway: Towards a Therapeutic Approach" was held at the Renaissance Orlando at SeaWorld Hotel (August 2-4, 2013). Seventy-one physicians and scientists attended the meeting, and parallel meetings were held by patient advocacy groups (CFC International, Costello Syndrome Family Network, NF Network and Noonan Syndrome Foundation). Parent and patient advocates opened the meeting with a panel discussion to set the stage regarding their hopes and expectations for therapeutic advances. In keeping with the theme on therapeutic development, the sessions followed a progression from description of the phenotype and definition of therapeutic endpoints, to definition of genomic changes, to identification of therapeutic targets in the RAS/MAPK pathway, to preclinical drug development and testing, to clinical trials. These proceedings will review the major points of discussion.
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    Rapidly progressive hypertrophic cardiomyopathy in an infant with Noonan syndrome with multiple lentigines: Palliative treatment with a rapamycin analog
    (Wiley-Blackwell, 2015) Hahn, Andreas; Lauriol, J; Thul, Josef; Behnke-Hall, Kachina; Logeswaran, Tushiha; Schänzer, Anne; Bögürcü, Nuray; Garvalov, Boyan K.; Zenker, Martin; Gelb, Bruce D.; von Gerlach, Susanne; Kandolf, Reinhard; Kontaridis, Maria; Schranz, Dietmar
    Noonan syndrome with multiple lentigines (NSML) frequently manifests with hypertrophic cardiomyopathy (HCM). Recently, it was demonstrated that mTOR inhibition reverses HCM in NSML mice. We report for the first time on the effects of treatment with a rapamycin analog in an infant with LS and malignant HCM. In the boy, progressive HCM was diagnosed during the first week of life and a diagnosis of NSML was established at age 20 weeks by showing a heterozygous Q510E mutation in PTPN11. Immunoblotting with antibodies against pERK, pAkt, and pS6RP in fibroblasts demonstrated enhanced Akt/mTOR pathway activity. Because of the patient's critical condition, everolimus therapy was started at age 24 weeks and continued until heart transplantation at age 36 weeks. Prior to surgery, heart failure improved from NYHA stage IV to II and brain natriuretic peptide values decreased from 9,600 to <1,000 pg/ml, but no reversal of cardiac hypertrophy was observed. Examination of the explanted heart revealed severe hypertrophy and myofiber disarray with extensive perivascular fibrosis. These findings provide evidence that Akt/mTOR activity is enhanced in NSML with HCM and suggest that rapamycin treatment could principally be feasible for infantile NSML. The preliminary experiences made in this single patient indicate that therapy should start early to prevent irreversible cardiac remodelling.
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    In vivo efficacy of the AKT inhibitor ARQ 092 in Noonan Syndrome with multiple lentigines-associated hypertrophic cardiomyopathy
    (Public Library of Science, 2017) Wang, Jianxun; Chandrasekhar, Vasanth; Abbadessa, Giovanni; Yu, Yi; Schwartz, Brian; Kontaridis, Maria
    Noonan Syndrome with Multiple Lentigines (NSML, formerly LEOPARD syndrome) is an autosomal dominant "RASopathy" disorder manifesting in congenital heart disease. Most cases of NSML are caused by catalytically inactivating mutations in the protein tyrosine phosphatase (PTP), non-receptor type 11 (PTPN11), encoding the SH2 domain-containing PTP-2 (SHP2) protein. We previously generated knock-in mice harboring the PTPN11 mutation Y279C, one of the most common NSML alleles; these now-termed SHP2Y279C/+ mice recapitulate the human disorder and develop hypertrophic cardiomyopathy (HCM) by 12 weeks of age. Functionally, heart and/or cardiomyocyte lysates from SHP2Y279C/+ mice exhibit increased basal and agonist-induced AKT and mTOR activities. Here, we sought to determine whether we could reverse the hypertrophy in SHP2Y279C/+ mice using ARQ 092, an oral and selective allosteric AKT inhibitor currently in clinical trials for patients with PI3K/AKT-driven tumors or Proteus syndrome. We obtained echocardiographs of SHP2Y279C/+ and wildtype (SHP2+/+) littermates, either in the presence or absence of ARQ 092 at 12, 14, and 16 weeks of age. While SHP2Y279C/+ mice developed significant left ventricular hypertrophy by 12 weeks, as indicated by decreased chamber dimension and increased posterior wall thickness, treatment of SHP2Y279C/+ mice with ARQ 092 normalized the hypertrophy in as early as 2 weeks following treatment, with hearts comparable in size to those in wildtype (SHP2+/+) mice. In addition, we observed an increase in fractional shortening (FS%) in SHP2Y279C/+ mice, an effect of increased compensatory hypertrophy, which was not apparent in SHP2Y279C/+ mice treated with ARQ 092, suggesting functional improvement of HCM upon treatment with the AKT inhibitor. Finally, we found that ARQ 092 specifically inhibited AKT activity, as well as its downstream effectors, PRAS and S6RP in NSML mice. Taken together, these data suggest ARQ 092 may be a promising novel therapy for treatment of hypertrophy in NSML patients.
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    A Cross-Species Study of PI3K Protein-Protein Interactions Reveals the Direct Interaction of P85 and SHP2
    (Nature Publishing Group, 2016) Breitkopf, Susanne B.; Yang, Xuemei; Begley, Michael J.; Kulkarni, Meghana; Chiu, Yu-Hsin; Turke, Alexa B.; Lauriol, J; Yuan, Min; Qi, Jie; Engelman, Jeffrey A; Hong, Pengyu; Kontaridis, Maria; Cantley, Lewis C.; Perrimon, Norbert; Asara, John
    Using a series of immunoprecipitation (IP) – tandem mass spectrometry (LC-MS/MS) experiments and reciprocal BLAST, we conducted a fly-human cross-species comparison of the phosphoinositide-3-kinase (PI3K) interactome in a drosophila S2R+ cell line and several NSCLC and human multiple myeloma cell lines to identify conserved interacting proteins to PI3K, a critical signaling regulator of the AKT pathway. Using H929 human cancer cells and drosophila S2R+ cells, our data revealed an unexpected direct binding of Corkscrew, the drosophila ortholog of the non-receptor protein tyrosine phosphatase type II (SHP2) to the Pi3k21B (p60) regulatory subunit of PI3K (p50/p85 human ortholog) but no association with Pi3k92e, the human ortholog of the p110 catalytic subunit. The p85-SHP2 association was validated in human cell lines, and formed a ternary regulatory complex with GRB2-associated-binding protein 2 (GAB2). Validation experiments with knockdown of GAB2 and Far-Western blots proved the direct interaction of SHP2 with p85, independent of adaptor proteins and transfected FLAG-p85 provided evidence that SHP2 binding on p85 occurred on the SH2 domains. A disruption of the SHP2-p85 complex took place after insulin/IGF1 stimulation or imatinib treatment, suggesting that the direct SHP2-p85 interaction was both independent of AKT activation and positively regulates the ERK signaling pathway.
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    SHP-2 Positively Regulates Myogenesis by Coupling to the Rho GTPase Signaling Pathway
    (American Society for Microbiology, 2004) Kontaridis, Maria; Eminaga, S.; Fornaro, M.; Zito, C. I.; Sordella, R.; Settleman, Jeffrey Evan; Bennett, A. M.
    Myogenesis is an intricate process that coordinately engages multiple intracellular signaling cascades. The Rho family GTPase RhoA is known to promote myogenesis, however, the mechanisms controlling its regulation in myoblasts have yet to be fully elucidated. We show here that the SH2-containing protein tyrosine phosphatase, SHP-2, functions as an early modulator of myogenesis by regulating RhoA. When MyoD was expressed in fibroblasts lacking functional SHP-2, muscle-specific gene activity was impaired and abolition of SHP-2 expression by RNA interference inhibited muscle differentiation. By using SHP-2 substrate-trapping mutants, we identified p190-B RhoGAP as a SHP-2 substrate. When dephosphorylated, p190-B RhoGAP has been shown to stimulate the activation of RhoA. During myogenesis, p190-B RhoGAP was tyrosyl dephosphorylated concomitant with the stimulation of SHP-2's phosphatase activity. Moreover, overexpression of a catalytically inactive mutant of SHP-2 inhibited p190-B RhoGAP tyrosyl dephosphorylation, RhoA activity, and myogenesis. These observations strongly suggest that SHP-2 dephosphorylates p190-B RhoGAP, leading to the activation of RhoA. Collectively, these data provide a mechanistic basis for RhoA activation in myoblasts and demonstrate that myogenesis is critically regulated by the actions of SHP-2 on the p190-B Rho GAP/RhoA pathway.
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    Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome–associated PTPN11 mutation
    (American Society for Clinical Investigation, 2011) Marin, Talita M.; Keith, Kimberly; Davies, Benjamin; Conner, David; Guha, Prajna; Kalaitzidis, Demetrios; Wu, Xue; Lauriol, J; Wang, Bo; Bauer, Michael; Bronson, Roderick; Franchini, Kleber G.; Neel, Benjamin G.; Kontaridis, Maria
    LEOPARD syndrome (LS) is an autosomal dominant “RASopathy” that manifests with congenital heart disease. Nearly all cases of LS are caused by catalytically inactivating mutations in the protein tyrosine phosphatase (PTP), non-receptor type 11 (PTPN11) gene that encodes the SH2 domain-containing PTP-2 (SHP2). RASopathies typically affect components of the RAS/MAPK pathway, yet it remains unclear how PTPN11 mutations alter cellular signaling to produce LS phenotypes. We therefore generated knockin mice harboring the Ptpn11 mutation Y279C, one of the most common LS alleles. Ptpn11Y279C/+ (LS/+) mice recapitulated the human disorder, with short stature, craniofacial dysmorphia, and morphologic, histologic, echocardiographic, and molecular evidence of hypertrophic cardiomyopathy (HCM). Heart and/or cardiomyocyte lysates from LS/+ mice showed enhanced binding of Shp2 to Irs1, decreased Shp2 catalytic activity, and abrogated agonist-evoked Erk/Mapk signaling. LS/+ mice also exhibited increased basal and agonist-induced Akt and mTor activity. The cardiac defects in LS/+ mice were completely reversed by treatment with rapamycin, an inhibitor of mTOR. Our results demonstrate that LS mutations have dominant-negative effects in vivo, identify enhanced mTOR activity as critical for causing LS-associated HCM, and suggest that TOR inhibitors be considered for treatment of HCM in LS patients.
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    RhoA signaling in cardiomyocytes protects against stress-induced heart failure but facilitates cardiac fibrosis
    (American Association for the Advancement of Science (AAAS), 2014) Lauriol, J; Keith, K.; Jaffre, Fabrice; Couvillon, A.; Saci, A.; Goonasekera, S. A.; McCarthy, Jason; Kessinger, Chase; Wang, Jeffrey; Ke, Q; Kang, Peter; Molkentin, J. D.; Carpenter, C.; Kontaridis, Maria
    The Ras-related guanosine triphosphatase RhoA mediates pathological cardiac hypertrophy, but also promotes cell survival and is cardioprotective after ischemia/reperfusion injury. To understand how RhoA mediates these opposing roles in the myocardium, we generated mice with a cardiomyocyte-specific deletion of RhoA. Under normal conditions, the hearts from these mice showed functional, structural, and growth parameters similar to control mice. Additionally, the hearts of the cardiomyocyte-specific, RhoA-deficient mice subjected to transverse aortic constriction (TAC)-a procedure that induces pressure overload and, if prolonged, heart failure-exhibited a similar amount of hypertrophy as those of the wild-type mice subjected to TAC. Thus, neither normal cardiac homeostasis nor the initiation of compensatory hypertrophy required RhoA in cardiomyocytes. However, in response to chronic TAC, hearts from mice with cardiomyocyte-specific deletion of RhoA showed greater dilation, with thinner ventricular walls and larger chamber dimensions, and more impaired contractile function than those from control mice subjected to chronic TAC. These effects were associated with aberrant calcium signaling, as well as decreased activity of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and AKT. In addition, hearts from mice with cardiomyocyte-specific RhoA deficiency also showed less fibrosis in response to chronic TAC, with decreased transcriptional activation of genes involved in fibrosis, including myocardin response transcription factor (MRTF) and serum response factor (SRF), suggesting that the fibrotic response to stress in the heart depends on cardiomyocyte-specific RhoA signaling. Our data indicated that RhoA regulates multiple pathways in cardiomyocytes, mediating both cardioprotective (hypertrophy without dilation) and cardio-deleterious effects (fibrosis). The Ras-related guanosine triphosphatase RhoA mediates pathological cardiac hypertrophy, but also promotes cell survival and is cardioprotective after ischemia/reperfusion injury. To understand how RhoA mediates these opposing roles in the myocardium, we generated mice with a cardiomyocyte-specific deletion of RhoA. Under normal conditions, the hearts from these mice showed functional, structural, and growth parameters similar to control mice. Additionally, the hearts of the cardiomyocyte-specific, RhoA-deficient mice subjected to transverse aortic constriction (TAC)-a procedure that induces pressure overload and, if prolonged, heart failure-exhibited a similar amount of hypertrophy as those of the wild-type mice subjected to TAC. Thus, neither normal cardiac homeostasis nor the initiation of compensatory hypertrophy required RhoA in cardiomyocytes. However, in response to chronic TAC, hearts from mice with cardiomyocyte-specific deletion of RhoA showed greater dilation, with thinner ventricular walls and larger chamber dimensions, and more impaired contractile function than those from control mice subjected to chronic TAC. These effects were associated with aberrant calcium signaling, as well as decreased activity of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and AKT. In addition, hearts from mice with cardiomyocyte-specific RhoA deficiency also showed less fibrosis in response to chronic TAC, with decreased transcriptional activation of genes involved in fibrosis, including myocardin response transcription factor (MRTF) and serum response factor (SRF), suggesting that the fibrotic response to stress in the heart depends on cardiomyocyte-specific RhoA signaling. Our data indicated that RhoA regulates multiple pathways in cardiomyocytes, mediating both cardioprotective (hypertrophy without dilation) and cardio-deleterious effects (fibrosis).
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    SHP-2 complex formation with the SHP-2 substrate-1 during C2C12 myogenesis
    (Company of Biologists, 2001) Kontaridis, Maria; Liu, Xiangdong; Zhang, Lang; Bennett, Anton
    Myogenesis is a highly ordered process that involves the expression of muscle-specific genes, cell-cell recognition and multinucleated myotube formation. Although protein tyrosine kinases have figured prominently in myogenesis, the involvement of tyrosine phosphatases in this process is unknown. SHP-2 is an SH2 domain-containing tyrosine phosphatase, which positively regulates growth and differentiation. We show that in C2C12 myoblasts, SHP-2 becomes upregulated early on during myogenesis and associates with a 120 kDa tyrosyl-phosphorylated complex. We have identified that the 120 kDa complex consists of the SHP-2 substrate-1 (SHPS-1) and the Grb2-associated binder-1 (Gab-1). SHPS-1, but not Gab-1, undergoes tyrosyl phosphorylation and association with SHP-2 during myogenesis, the kinetics of which correlate with the expression of MyoD. Either constitutive expression or inducible activation of MyoD in 10T(1/2) fibroblasts promotes SHPS-1 tyrosyl phosphorylation and its association with SHP-2. It has been shown that p38 mitogen-activated protein kinase (MAPK) activity is required for the expression/activation of MyoD and MyoD-responsive genes. Inhibition of p38 MAPK by SB203580 in differentiating C2C12 myoblasts blocks MyoD expression, SHPS-1 tyrosyl phosphorylation and the association of SHPS-1 with SHP-2. These data suggest that SHPS-1/SHP-2 complex formation is an integral signaling component of skeletal muscle differentiation.
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    Role of SHP-2 in Fibroblast Growth Factor Receptor-Mediated Suppression of Myogenesis in C2C12 Myoblasts
    (American Society for Microbiology, 2002) Kontaridis, Maria; Liu, X.; Zhang, L.; Bennett, A. M.
    Ligand activation of the fibroblast growth factor receptor (FGFR) represses myogenesis and promotes activation of extracellular signal-regulated kinases 1 and 2 (Erks). The precise mechanism through which the FGFR transmits both of these signals in myoblasts remains unclear. The SH2 domain-containing protein tyrosine phosphatase, SHP-2, has been shown to participate in the regulation of FGFR signaling. However, no role for SHP-2 in FGFR myogenic signaling is known. In this study, we show that stimulation of C2C12 myoblasts with FGF-2 induces SHP-2 complex formation with tyrosyl-phosphorylated FGFR substrate 2α (FRS-2α). Both the catalytic activity and, to a much lesser extent, the Grb2 binding-tyrosyl phosphorylation sites of SHP-2 are required for maximal FGF-2-induced Erk activity and Elk-1 transactivation. When overexpressed in C2C12 myoblasts, wild-type SHP-2, but not a catalytically inactive SHP-2 mutant, potentiates the suppressive effects of FGF-2 on muscle-specific gene expression. In addition, expression of a constitutively active mutant of SHP-2 is sufficient to prevent myogenesis. The constitutively active mutant of SHP-2 induces hyper-tyrosyl phosphorylation of FRS-2α but fails to stimulate or potentiate either FGF-2-induced Erk activation or Elk-1 transactivation. These data suggest that in myoblasts, SHP-2 represses myogenesis via a pathway that is independent of the Erks. We propose that SHP-2 plays a pivotal role in FGFR signaling in myoblasts via both Erk-dependent and Erk-independent pathways.
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    PZR Coordinates Shp2 Noonan and LEOPARD Syndrome Signaling in Zebrafish and Mice
    (American Society for Microbiology, 2014) Paardekooper Overman, J.; Yi, J.-S.; Bonetti, M.; Soulsby, M.; Preisinger, C.; Stokes, Marquita Lavelle; Hui, L.; Silva, J. C.; Overvoorde, J.; Giansanti, P.; Heck, A. J. R.; Kontaridis, Maria; den Hertog, J.; Bennett, A. M.
    Noonan syndrome (NS) is an autosomal dominant disorder caused by activating mutations in the PTPN11 gene encoding Shp2, which manifests in congenital heart disease, short stature, and facial dysmorphia. The complexity of Shp2 signaling is exemplified by the observation that LEOPARD syndrome (LS) patients possess inactivating PTPN11 mutations yet exhibit similar symptoms to NS. Here, we identify “protein zero-related” (PZR), a transmembrane glycoprotein that interfaces with the extracellular matrix to promote cell migration, as a major hyper-tyrosyl-phosphorylated protein in mouse and zebrafish models of NS and LS. PZR hyper-tyrosyl phosphorylation is facilitated in a phosphatase-independent manner by enhanced Src recruitment to NS and LS Shp2. In zebrafish, PZR overexpression recapitulated NS and LS phenotypes. PZR was required for zebrafish gastrulation in a manner dependent upon PZR tyrosyl phosphorylation. Hence, we identify PZR as an NS and LS target. Enhanced PZR-mediated membrane recruitment of Shp2 serves as a common mechanism to direct overlapping pathophysiological characteristics of these PTPN11 mutations.