A sinalização celular é a resposta adaptativa da célula a um estímulo extracelular. A transdução do sinal no interior da célula e a resposta final a esse sinal envolvem interações proteína-proteína e reações de fosforilação e desfosforilação de proteínas mediadas por quinases e fosfatases, respectivamente. A fosforilação de proteínas é a transferência do grupo fosforila do ATP para aminoácidos específicos, normalmente para serinas, treoninas e tirosinas em eucariotos. A desfosforilação é a remoção do grupo fosforila desses aminoácidos. Essas reações são chave nas células e fazem parte tanto de processos fisiológicos quanto patológicos.
No genoma humano encontramos pelo menos 500 quinases. Em diversas patologias inclusive na dor aguda e crônica encontramos alterações nas atividades destas enzimas , tornando-as bons alvos terapêuticos. De fato, as empresas farmacêuticas têm dedicado vários esforços para encontrar novos moduladores específicos das diferentes quinases, o que tem sido uma tarefa extremamente difícil devido à conservação destas enzimas, o que limita a especificidade de ação destes moduladores.
O principal objetivo do laboratório é compreender as vias de sinalização envolvidas na dor para o desenvolvimento de analgésicos não-opioides. Visamos estudar as vias de sinalização envolvidas na embriogênese das vias da dor, e na transmissão de sinais da dor inflamatória pelo fator de crescimento neural NGF ativando a quinase TrkA, e o papel da PKMz nos processos de remodelamento das sinapses na dor crônica.
Projetos principais
I. Aprendendo com os pacientes:
Esse projeto visa compreender como mutações na quinase TrkA em pacientes que não sentem dor alteram as vias de sinalização que levam à dor e o efeito dessas mutações no desenvolvimento do sistema nervoso sensorial. Com base nessas mutações estamos desenvolvendo e caracterizando novos moduladores farmacológicos para a dor.
II. Remodelamento das sinapses
A quinase PKMz, expressa especificamente no sistema nervoso, está envolvida no remodelamento de sinapses. Desejamos determinar os fatores epigenéticos e as vias de sinalização que modulam a expressão desta quinase, bem como seu papel no remodelamento das sinapses na dor crônica. A identificação das proteínas parceiras e dos substratos desta quinase poderá auxiliar na compreensão do processo de desenvolvimento de dor crônica.
Inglês
Cell signaling is the adaptive response of a cell to an extracellular stimulus. Signal transduction inside the cell and the final cellular response to the signal is mediated mainly by protein-protein interactions and phosphorylation and dephosphorylation led by kinases and phosphatases, respectively. Protein phosphorylation is the transfer of a phosphoryl group from ATP to specific amino acid residues including serine, threonine and tyrosine in eukaryotes. Dephosphorylation is the removal of the phosphoryl group from these amino acids. These are key reactions in cells and are part of physiological and pathological processes.
In the human genome there are at least 500 kinases. In several pathologies including acute and chronic pain we find alterations in the activity of these enzymes,., making them good therapeutic targets. In fact, the pharmaceutical industry has dedicated a large effort to find new specific modulators for different kinases. This has been challenging due to the conservation of these enzymes limiting the specificity of the modulators.
The main goal of the laboratory is to understand the signaling pathways that lead to pain to guide the development of new non-opioid analgesics. We aim to study signaling pathways involved in the embryogenesis of components of thepain system and , the signal transduction processes involved in inflammatory pain mediated by Nerve Growth factor (NGF) and the kinase activated by this growth factor, TrkA as well as the role of the kinase PKMz in synaptic remodeling in chronic pain.
Main Projects
I. Learning from the patients:
This project aims to understand how mutations found in TrkA kinase in patients that don´t feel pain, alter signal transduction pathways leading to pain and the development of the sensory nervous system. Based on these mutations we are developing and characterized new analgesic leads for pain.
II. Synaptic remodeling:
The kinase PKMz, is expressed specifically in the nervous system and involved in synaptic remodeling. We aim to determine the epigenetic factors and signaling pathways that modulate the expression of this kinase as well as its role in synaptic remodeling in chronic pain. Identifying PKMz substrates and binding proteins can help understand the process of development of chronic pain.
Publicações recentes do laboratório:
- Structural analysis of TrkA mutations in patients with congenital insensitivity to pain reveals PLCγ as an analgesic drug target. Beatriz C. Moraes, Helder V. Ribeiro-Filho, Allan P. Roldão , Elaine F. Toniolo , Gustavo P. B. Carretero, Germán G. Sgro, Fernanda A. H. Batista, Damian E. Berardi, Victoria R. S. Oliveira , Rebeka Tomasin, Felipe M. Vieceli , Dimitrius T. Pramio, Alexandre B. Cardoso, Ana C. M. Figueira, Shaker C. Farah, Lakshmi A. Devi , Camila S. Dale , Paulo S. L. de Oliveira and Deborah Schechtman. Science Signaling, 26 Apr 2022, Vol 15, Issue 731. DOI: 10.1126/scisignal.abm6046
- Exploring Morphine-Triggered PKC-Targets and Their Interaction with Signaling Pathways Leading to Pain via TrkA. Duarte, ML. ; Pramio, DT. ; Devi, LA. & Schechtman, D.. Proteomes, 2018 v. 6, p. 39.
- Generating conformation specific poly and monoclonal anti-Protein kinase C antibodies. Pena, DA., Pacheco, DMV., Oliveira, PSL. Alves, MJM. & Schechtman, D.. Current Protocols in Chemical Biology, 2018 v. 1, p. e42.
- “Revisiting protein kinase–substrate interactions: Toward therapeutic development” Oliveira PS, Ferraz FAN, Pena DA, Pramio DT, Morais FA & Deborah Schechtman. Sci, Signal. 22 Mar, 2016 Re3
- “Rational design and validation of an anti-protein kinase C active-state specific antibody based on conformational changes.” Pena DA, Andrade VP, Silva GÁ, Neves JI, Oliveira PS, Alves MJ, Devi LA & Schechtman D. Sci Rep. 2016 Feb 25;6:22114.
- “Protein folding creates structure-based, noncontiguous consensus phosphorylation motifs recognized by kinases”.Duarte ML, Pena DA, Nunes Ferraz FA, Berti DA, Paschoal Sobreira TJ, Costa-Junior HM, Abdel Baqui MM, Disatnik MH, Xavier-Neto J, Lopes de Oliveira OS & Schechtman D. Sci Signal. 2014 Nov 4;7(350):ra105.
- “Activation of protein kinase C delta by ψδRACK peptide promotes embryonic stem cell proliferation through ERK 1/2. Garavello NM, Pena DA, Bonatto JM, Duarte ML, Costa-Junior HM, Schumacher RI, Forti FL & Schechtman D. J Proteomics. 2013 Dec 6;94:497-512.
- Phosphoproteomics profiling suggests a role for nuclear βΙPKC in transcription processes of undifferentiated murine embryonic stem cells. Costa-Junior HM, Garavello NM, Duarte ML, Berti DA, Glaser T, de Andrade A, Labate CA, Ferreira AT, Perales JE, Xavier-Neto J, Krieger JE, Schechtman D. J Proteome Res. 2010 Dec 3;9(12):6191-206.
- Specific modulation of protein kinase activity via small peptides.Costa-Junior HM, Suetsugu MJ, Krieger JE & Schechtman D. Regul Pept. 2009 Feb 25;153(1-3):11-8. doi: 10.1016/j.regpep.2008.12.002. Epub 2008 Dec 16. Review.
Colaborações e outras publicações
Colaborations and other publications
- Naressi RG.; Schechtman D. and Malnic B. “Odorant receptors as potential drug targets. Trends Pharmacol Sci. 2022 Aug 20:S0165-6147(22)00174-2.
- Sbrana, MF.; Fornazieri, MA.; Bruni-Cardoso, A.; Avelino-Silva VI.; Schechtman, D.; Voegels, RL.; Malnic, B.; Glezer, I. & De Rezende, FP. “Olfactory Dysfunction in Frontline Health Care Professionals During COVID-19 Pandemic in Brazil”. Frontiers in Physiology, v. 12, p. 622987, 2021.
- Russo LC.; Tomasin, R.; Matos, IA.; Manucci, AC.; Sowa, ST.; Dale, K.; Caldecott, KW.; Lehtio,L.; Schechtman, D.; Meotti, FC.; Bruni-Cardoso, A. & Hoch, NC. “The SARS-CoV-2 Nsp3 macrodomain reverses PARP9/DTX3L-dependent ADP-ribosylation induced by interferon signaling. Journal of Biological Chemistry v. 297, p. 101041, 2021.
- Lemos Duarte M.; Trimbake NA.; Gupta A.; Tumanut C.; Fan X, Woods C, Ram A, Gomes I, Bobeck EN., Schechtman D., Devi LA “High-throughput screening and validation of antibodies against synaptic proteins to explore opioid signaling dynamics”.Commun Biol. 2021 Feb 22;4(1):238.
- Glezer, I.; Bruni-Cardoso, A.; Schechtman, D. & Malnic, B. “Viral infection and smell loss: The case of COVID19”. Journal of Neurochemistry, v. 24, p. 10.1111, 2020.
- De Miranda, MC.; Rodrigues, MA.; De Angelis, ACC; Faria, JAQA.; Kunarth-LIMA, M.; Mignery, GA.; Schechtman, D.; Goes, AM.; Nathanson, MH & Gomes, DA.“Epidermal growth factor (EGF) triggers nuclear calcium signaling through the intranuclear phospholipase C delta-4 (PLCd)”. Journal of Biological Chemistry. v.294, p.16650 - 16662, 2019.
- Baptista, MS.; Alves, MJM.; Arantes, GM.; Armelin, HA.; Augisto, O.; Baldini, RL.; Basseres, DS.; Bechara, EJH.; Bruni-Cardoso, A.; Chaimovich, H.; Colepicolo Neto, P.; Colli, W.; Cuccovia, IM.; Da-Silva, AM.; Di Mascio, P.; Farah, SC.; Ferreira, C.; Forti, FL.; Giordano, RJ.; Gomes, SL.; Gueiros Filho, FJ.; Hoch, NC.; Hotta, CT.; Labriola, L.; Lameu, C.; Machini, MT.; Malnic, B.; Marana, SR.; Medeiros, MHG.; Meotti, FC.; Miyamoto, S.; Oliveira, CC.; Souza-Pinto, NC.; Reis, EM.; Ronsein, GE.; Salinas, RK.; Schechtman, D.,; Verjovski-Almeida, S.; Winck, FV.; Zingales, B.& Kowaltowski, AJ. “Where do we aspire to publish? A position paper on scientific communication in biochemistry and molecular biology”. Brazilian Journal of Medical and Biological Research (on line). v.52, p.1 - , 2019.
- Teixira FR.; Manfiolli AO.; Vieira, NA.; Medeiros, AC.; Coelho, P De O.; Santiago, DG.; Schechtman, D. & Gomes, MD. “FBXO25 regulates MAPK signaling pathway through inhibition of ERK1/2 phosphorylation”. Archives of Biochemistry and Biophysics v.621, p.38 - 45, 2017.
- Qvit, N.; Schechtman, D.; Pena, DA.; Berti, DA.; Soares, CO.; Miao, Q.; Liang, L.; Baron, LA.; Teh-Poot, C.; Martínez-Vega, P.; Ramirez-Sierra, MJ.; Churchill, E; Cinningham, AD.; Malkovskiy, AV.; Federspiel, NA.; Gozzo, FC.; Torrecilhas, AC.; Alves, MJM.; Jardim A.;Momar, N.; Dumonteil E. & Mochly-Rosen, D. “Scaffold Proteins LACK and TRACK as Potential Drug Targets in Kinetoplastid Parasites: Development of Inhibitors”. International Journal for Parasitology: Drugs and Drug resistance., v.6, p.74 - 84, 2016.
- Oliveira, KC.; Carvalho, MLP.; Bonatto, JMC.; Schechtman, D. & Verjovski-Almeida, S. “Human TNF-a; induces differential protein phosphorylation in Schistosoma mansoni adult male worms”. Parasitology Research (1987. Internet). , v.115, p.817 - 828, 2015.
- Santos, AM.; Schechtman, D.; Cardoso, AC.; Clemente, CFMZ.; Silva, JC.; Fioramonte, M.; Pereira, MB M.; Marin, TM.; De Oliveira, PSL.; Figueira, ACM.; Oliveira, SHP.; Torriani, ÍL.; Gozzo, FC.; Xavier-Neto J.; & Franchini, KG. “FERM domain interaction with myosin negatively regulates FAK in cardiomyocyte hypertrophy”. Nature Chemical Biology. v.8, p.102 - 110, 2011.
- Azambuja, AP.; Portillo-Sanchez, V.; Rodrigues, MV.; Omae, SV.; Schechtman, D.; Strauss, BE.; Costanzi-Strauss, E.; Krieger, JE.; Perez-Pomares, JM. & Xavier-Neto, J. “Retinoic Acid and VEGF Delay Smooth Muscle Relative to Endothelial Differentiation to Coordinate Inner and Outer Coronary Vessel Wall Morphogenesis”. Circulation Research. v.107, p.204 - 216, 2010.
- Sobreira, TJP.; Marlletaz, F.; Simões-Costa, M.; Schechtman, D.; Pereira, AC.; Brunet, F.; Sweeney, S.; Pani, A.; Aronowicz, J.; Lowe, CJ.; Davidson, B.; Laudet, V.; Bronner, M.; De Oliveira, PSL.; Schubert, M. & Xavier-Neto, J. “Structural shifts of aldehyde dehydrogenase enzymes were instrumental for the early evolution of retinoid-dependent axial patterning in metazoans”. Proceedings of the National Academy of Sciences of the United States of America. v.108, p.226 - 231, 2010.
- Kheifets, V.; Bright, R.; Inagaki, K; Shechtman, D. & Mochly-Rosen, D.“Protein Kinase C (PKC)-Annexin V Interaction: A required step in PKC translocation and function”. The Journal of Biological Chemistry (Print). v.281, p.23218 - 23226, 2006. (72 Citations Google Scholar)
- Shechtman, D., Craske, ML.; Kheifets, V.; Meyer, T.; Schechtman, J. & Mochly-Rosen, D.“A critical intramolecular interaction for protein kinase C epsilon translocation”. The Journal of Biological Chemistry (Print). v.16, p.15831 - 15840, 2004.
- Souroujon, MC.; Yao, L.; Chen, H.; Endemann, G.; Khaner, H.; Geeraert, V.; Schechtman, D.; Gordon, AS.; Diamond, I.; Mochly-Rosen, D. “State-specific monoclonal antibodies identify an intermediate state in epsilon protein kinase C activation.” The Journal of Biological Chemistry (Print). v.23, p.17617 - 17624, 2004.
- Endemann, G.; Schechtman, D.; Mochly-Rosen, D.“Cytotoxicity of pEGFP vector is due to residues encoded by the multiple cloning site”. Analytical Biochemistry (Print). v.15, p.345 - 347, 2003.
- Schechtman, D. & Mochly-Rosen, D. “Isozyme specific inhibitors and activators of PKC”. Methods In Enzymology. v.345, p.470 - 489, 2002. (68 Citations Google Scholar).
- Schechtman, D. & Mochly-Rosen, D. “Adaptor proteins in protein kinase C-mediated signal transduction”. Oncogene (Basingstoke). v.20, p.6339 - 6347, 2001.
- Schechtman, D.; Winnen, R.; Tarrab-Hazadai, R.; Ram, D.; Shinder, V.; Grevelding, C.; Kunz, W. & Arnon, R “Expression and immunolocalization of the 14-3-3 protein of Schistosoma mansoni”. Parasitology (London), v.123, p.573 - 582, 2001.
- Chen, L.; Hahn, H.; Wu, G.; Chen, C.; Liron, T.; Schechtman, D.; Cavallaro, G.; Banci, L.; Guo, Y.; Bolli, R.; DornII, GW. & Mochly-Rosen, D. “Opposing Cardioprotective Actions and parallel hypertrophic effects of PKC and PKC”. Proceedings of the National Academy of Sciences of the United States of America, v.25, p.11114 - 11119, 2001.
- Mochly-Rosen, D.; Fagin, JA.; Knauf, JA.; Nikirov, Y.; Liron, T.& Schechtman, D. “Spontaneous occurrence of an inhibitor of protein kinase C localization in a thyroid cancer cell line: role in thyroid tumorigenesis”. Advances In Enzyme Regulation. v.41, p.87 - 97, 2001.
- Schechtman, D.; Tarrab-Hazdai, R.& Arnon, R. “The 14-3-3 protein as a vaccine candidate against schistosomiasis”. Parasite Immunology (Print). v.4, p.213 - 217, 2001
- Ben-Yedidia, T.; Tarrab-Hazdai, R.; Schechtman, D. & Arnon, R.“Intranasal administration of synthetic recombinant peptide-based vaccine protects mice against infection by Schistosoma mansoni”. Infection and Immunity. v.67, p.4360 - 4366, 1999.
- Tarrab-Hazdai, R.; Schechtman, D.; Lowell, G.; PirakI, E. & Arnon, R. “Proteosome delivery of a protective 9B-antigen against Schistosoma mansoni”. International Journal of Immunopharmacology. v.21, p.205 - 218, 1999.
- Tarrab-Hazdai, R.; Schechtman, D.& Arnon, R. “Synthesis and characterization of a protective peptide-based vaccine against Schistosoma mansoni.” Infection and Immunity. v.66, p.4526 - 4530, 1998.
- Tarrab-Hazdai, R.; Camacho, M.; Mendelovic, F. & Schechtman, D. An association between activity of the Na/K-pump and resistance of Schistosoma mansoni towards complement-mediated killing. Parasite Immunology. v.19, p.395 - 400, 1997.
- Schechtman, D.; Ram, D.; Tarrab-Hazdai, R.; Arnon, R. & Schechter, I. “Stage-specific expression of the mRNA encoding a 14-3-3 protein during the life cycle of Schistosoma mansoni”. Molecular and Biochemical Parasitology. v.73, p.275 - 278, 1995.
- Petter, R.; Rosenblatt, S.; Schechtman, D.; Wellems, T. & Mirelman, D.“Electrophoretic Karyotype and Linkage groups of Entamoeba histolytica: Differences between pathogenic and nonpathogenic isolates”. Infection and Immunity. v.61, p.3574 - 3577, 1993.
- Barcinski, MA.; Schechtman, D.; Quintao, LG.; Costa, DA.; Soares, LRB.; Moreira, MEC & Charlab, R. “Granulocyte Macrophage Colony Stimulating Factor Increases the Infectivity of Leishmania (leishmania) amazonensis”. Protecting Promastigotes from Heat Shock Induced Death. Infection and Immunity. v.60, p.3523 - 35237, 1992.
- Charlab, R.; Blaineau, C.; Schechtman, D. & Barcinski, M. A. “Granulocyte-Macrophage Colony Stimulating Factor is a Growth Factor for Promastigotes of Leishmania mexicana amazonensis”. Journal of Protozoology. v.37, 1990.
Notícia
In the news
https://veja.abril.com.br/saude/pessoas-que-nao-sentem-dor-podem-ser-a-chave-para-novos-analgesicos/
https://revistagalileu.globo.com/Ciencia/Saude/noticia/2022/05/analise-de-mutacoes-geneticas-leva-descoberta-de-alvo-para-o-desenvolvimento-de-analgesicos.html
https://www.uol.com.br/vivabem/noticias/redacao/2022/05/06/estudo-mutacoes-geneticas-leva-a-descoberta-de-novo-alvo-para-analgesicos.htm
https://revistapesquisa.fapesp.br/em-pessoas-insensiveis-a-dor-a-sugestao-para-um-novo-analgesico/
https://dnyuz.com/2022/04/26/alternative-of-chronic-pain-medication-could-curb-the-opioid-crisis/
https://uk.news.yahoo.com/different-type-pain-medication-solve-183211712.html
https://www.technologynetworks.com/tn/news/mutations-in-people-who-cant-sweat-or-feel-pain-may-suggest-drug-targets-for-chronic-pain-360952
https://revistapesquisa.fapesp.br/origami-molecular/
Videos
https://www.redeciencia.tv.br/copy-of-debora-andrade
https://www.youtube.com/watch?v=DD8oP_F1z7w