PIK3CA and CCM mutations fuel cavernomas through a cancer-like mechanism.

Animals Animals, Newborn Class I Phosphatidylinositol 3-Kinases / genetics Disease Models, Animal Endothelial Cells / metabolism Gain of Function Mutation Hemangioma, Cavernous, Central Nervous System / blood supply Humans Kruppel-Like Factor 4 Kruppel-Like Transcription Factors / metabolism Loss of Function Mutation MAP Kinase Kinase Kinase 3 / metabolism Male Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors Mice Mutation Neoplasms / blood supply Sirolimus / pharmacology TOR Serine-Threonine Kinases / metabolism

Journal

Nature
ISSN: 1476-4687
Titre abrégé: Nature
Pays: England
ID NLM: 0410462

Informations de publication

Date de publication:
06 2021
Historique:
received: 25 08 2020
accepted: 16 04 2021
pubmed: 29 4 2021
medline: 13 8 2021
entrez: 28 4 2021
Statut: ppublish

Résumé

Vascular malformations are thought to be monogenic disorders that result in dysregulated growth of blood vessels. In the brain, cerebral cavernous malformations (CCMs) arise owing to inactivation of the endothelial CCM protein complex, which is required to dampen the activity of the kinase MEKK3

Identifiants

DOI: 10.1038/s41586-021-03562-8 PMID: 33910229 PMC: PMC8626098
pubmed: 33910229
doi: 10.1038/s41586-021-03562-8
pii: 10.1038/s41586-021-03562-8
pmc: PMC8626098
mid: NIHMS1718518
doi:

Substances chimiques

KLF4 protein, human 0
Klf4 protein, mouse 0
Kruppel-Like Factor 4 0
Kruppel-Like Transcription Factors 0
Class I Phosphatidylinositol 3-Kinases EC 2.7.1.137
PIK3CA protein, human EC 2.7.1.137
Pik3ca protein, mouse EC 2.7.1.137
Mechanistic Target of Rapamycin Complex 1 EC 2.7.11.1
TOR Serine-Threonine Kinases EC 2.7.11.1
MAP Kinase Kinase Kinase 3 EC 2.7.11.25
Sirolimus W36ZG6FT64

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

271-276

Subventions

Organisme : NINDS NIH HHS
ID : P01 NS092521
Pays : United States
Organisme : European Research Council
Pays : International
Organisme : NINDS NIH HHS
ID : F30 NS100252
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL007150
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS100949
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007171
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL102138
Pays : United States
Organisme : NHLBI NIH HHS
ID : F31 HL152738
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA014236
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM145449
Pays : United States
Organisme : NINDS NIH HHS
ID : F31 NS115256
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL094326
Pays : United States

Références

Cuttano, R. et al. KLF4 is a key determinant in the development and progression of cerebral cavernous malformations. EMBO Mol. Med. 8, 6–24 (2015).
pmcid: 4718159 doi: 10.15252/emmm.201505433
Zhou, Z. et al. Cerebral cavernous malformations arise from endothelial gain of MEKK3-KLF2/4 signalling. Nature 532, 122–126 (2016).
pubmed: 27027284 pmcid: 4864035 doi: 10.1038/nature17178
Renz, M. et al. Regulation of β1 integrin-Klf2-mediated angiogenesis by CCM proteins. Dev. Cell 32, 181–190 (2015).
pubmed: 25625207 doi: 10.1016/j.devcel.2014.12.016
Otten, C. et al. Systematic pharmacological screens uncover novel pathways involved in cerebral cavernous malformations. EMBO Mol. Med. 10, e9155 (2018).
pubmed: 30181117 pmcid: 6180302 doi: 10.15252/emmm.201809155
Tang, A. T. et al. Endothelial TLR4 and the microbiome drive cerebral cavernous malformations. Nature 545, 305–310 (2017).
pubmed: 28489816 pmcid: 5757866 doi: 10.1038/nature22075
Fischer, A., Zalvide, J., Faurobert, E., Albiges-Rizo, C. & Tournier-Lasserve, E. Cerebral cavernous malformations: from CCM genes to endothelial cell homeostasis. Trends Mol. Med. 19, 302–308 (2013).
pubmed: 23506982 doi: 10.1016/j.molmed.2013.02.004
Fisher, O. S. & Boggon, T. J. Signaling pathways and the cerebral cavernous malformations proteins: lessons from structural biology. Cell. Mol. Life Sci. 71, 1881–1892 (2014).
pubmed: 24287896 doi: 10.1007/s00018-013-1532-9
Plummer, N. W., Zawistowski, J. S. & Marchuk, D. A. Genetics of cerebral cavernous malformations. Curr. Neurol. Neurosci. Rep. 5, 391–396 (2005).
pubmed: 16131422 doi: 10.1007/s11910-005-0063-7
Al-Shahi Salman, R. et al. Untreated clinical course of cerebral cavernous malformations: a prospective, population-based cohort study. Lancet Neurol. 11, 217–224 (2012).
pubmed: 22297119 doi: 10.1016/S1474-4422(12)70004-2
Awad, I. A. & Polster, S. P. Cavernous angiomas: deconstructing a neurosurgical disease. J. Neurosurg. 131, 1–13 (2019).
pubmed: 31261134 pmcid: 6778695 doi: 10.3171/2019.3.JNS181724
Porter, P. J., Willinsky, R. A., Harper, W. & Wallace, M. C. Cerebral cavernous malformations: natural history and prognosis after clinical deterioration with or without hemorrhage. J. Neurosurg. 87, 190–197 (1997).
pubmed: 9254081 doi: 10.3171/jns.1997.87.2.0190
Boulday, G. et al. Developmental timing of CCM2 loss influences cerebral cavernous malformations in mice. J. Exp. Med. 208, 1835–1847 (2011).
pubmed: 21859843 pmcid: 3171098 doi: 10.1084/jem.20110571
Maddaluno, L. et al. EndMT contributes to the onset and progression of cerebral cavernous malformations. Nature 498, 492–496 (2013).
pubmed: 23748444 doi: 10.1038/nature12207
Detter, M. R., Snellings, D. A. & Marchuk, D. A. Cerebral cavernous malformations develop through clonal expansion of mutant endothelial cells. Circ. Res. 123, 1143–1151 (2018).
pubmed: 30359189 pmcid: 6205520 doi: 10.1161/CIRCRESAHA.118.313970
Malinverno, M. et al. Endothelial cell clonal expansion in the development of cerebral cavernous malformations. Nat. Commun. 10, 2761 (2019).
pubmed: 31235698 pmcid: 6591323 doi: 10.1038/s41467-019-10707-x
Ramírez-Zamora, A. & Biller, J. Brainstem cavernous malformations: a review with two case reports. Arq. Neuropsiquiatr. 67 (3B), 917–921 (2009).
pubmed: 19838533 doi: 10.1590/S0004-282X2009000500030
Castro, M. et al. CDC42 deletion elicits cerebral vascular malformations via increased MEKK3-dependent KLF4 expression. Circ. Res. 124, 1240–1252 (2019).
pubmed: 30732528 doi: 10.1161/CIRCRESAHA.118.314300
Hong, C. C. et al. Cerebral cavernous malformations are driven by ADAMTS5 proteolysis of versican. J. Exp. Med. 217, e20200140 (2020).
pubmed: 32648916 pmcid: 7537394 doi: 10.1084/jem.20200140
Lissbrant, I. F., Lissbrant, E., Persson, A., Damber, J. E. & Bergh, A. Endothelial cell proliferation in male reproductive organs of adult rat is high and regulated by testicular factors. Biol. Reprod. 68, 1107–1111 (2003).
pubmed: 12606411 doi: 10.1095/biolreprod.102.008284
Samuels, Y. et al. Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 7, 561–573 (2005).
pubmed: 15950905 doi: 10.1016/j.ccr.2005.05.014
Rodriguez-Laguna, L. et al. Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly. J. Exp. Med. 216, 407–418 (2019).
pubmed: 30591517 pmcid: 6363432 doi: 10.1084/jem.20181353
Castillo, S. D. et al. Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans. Sci. Transl. Med. 8, 332ra43 (2016).
pubmed: 27030595 pmcid: 5973268 doi: 10.1126/scitranslmed.aad9982
Castel, P. et al. Somatic PIK3CA mutations as a driver of sporadic venous malformations. Sci. Transl. Med. 8, 332ra42 (2016).
pubmed: 27030594 pmcid: 4962922 doi: 10.1126/scitranslmed.aaf1164
Luks, V. L. et al. Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA. J. Pediatr. 166, 1048–1054 (2015).
pubmed: 25681199 pmcid: 4498659 doi: 10.1016/j.jpeds.2014.12.069
Limaye, N. et al. Somatic activating PIK3CA mutations cuse venous malformation. Am. J. Hum. Genet. 97, 914–921 (2015).
pubmed: 26637981 pmcid: 4678782 doi: 10.1016/j.ajhg.2015.11.011
Storck, S. E. et al. Endothelial LRP1 transports amyloid-β(1-42) across the blood-brain barrier. J. Clin. Invest. 126, 123–136 (2016).
pubmed: 26619118 doi: 10.1172/JCI81108
Rigamonti, D. et al. Cerebral cavernous malformations. Incidence and familial occurrence. N. Engl. J. Med. 319, 343–347 (1988).
pubmed: 3393196 doi: 10.1056/NEJM198808113190605
Dogruluk, T. et al. Identification of variant-specific functions of PIK3CA by rapid phenotyping of rare mutations. Cancer Res. 75, 5341–5354 (2015).
pubmed: 26627007 pmcid: 4681596 doi: 10.1158/0008-5472.CAN-15-1654
Gault, J., Shenkar, R., Recksiek, P. & Awad, I. A. Biallelic somatic and germ line CCM1 truncating mutations in a cerebral cavernous malformation lesion. Stroke 36, 872–874 (2005).
pubmed: 15718512 doi: 10.1161/01.STR.0000157586.20479.fd
Akers, A. L., Johnson, E., Steinberg, G. K., Zabramski, J. M. & Marchuk, D. A. Biallelic somatic and germline mutations in cerebral cavernous malformations (CCMs): evidence for a two-hit mechanism of CCM pathogenesis. Hum. Mol. Genet. 18, 919–930 (2009).
pubmed: 19088123 doi: 10.1093/hmg/ddn430
McDonald, D. A. et al. Lesions from patients with sporadic cerebral cavernous malformations harbor somatic mutations in the CCM genes: evidence for a common biochemical pathway for CCM pathogenesis. Hum. Mol. Genet. 23, 4357–4370 (2014).
pubmed: 24698976 pmcid: 4103679 doi: 10.1093/hmg/ddu153
Xu, L. et al. Clonal evolution and changes in two AML patients detected with a novel single-cell DNA sequencing platform. Sci. Rep. 9, 11119 (2019).
pubmed: 31366893 pmcid: 6668401 doi: 10.1038/s41598-019-47297-z
Lopez-Ramirez, M. A. et al. Thrombospondin1 (TSP1) replacement prevents cerebral cavernous malformations. J. Exp. Med. 214, 3331–3346 (2017).
pubmed: 28970240 pmcid: 5679163 doi: 10.1084/jem.20171178
Marchi, S. et al. Defective autophagy is a key feature of cerebral cavernous malformations. EMBO Mol. Med. 7, 1403–1417 (2015).
pubmed: 26417067 pmcid: 4644374 doi: 10.15252/emmm.201505316
Abdulrauf, S. I., Kaynar, M. Y. & Awad, I. A. A comparison of the clinical profile of cavernous malformations with and without associated venous malformations. Neurosurgery 44, 41–46, discussion 46–47 (1999).
pubmed: 9894962 doi: 10.1097/00006123-199901000-00020
Tan, W. H. et al. The spectrum of vascular anomalies in patients with PTEN mutations: implications for diagnosis and management. J. Med. Genet. 44, 594–602 (2007).
pubmed: 17526801 pmcid: 2597949 doi: 10.1136/jmg.2007.048934
Adams, D. M. et al. Efficacy and safety of sirolimus in the treatment of complicated vascular anomalies. Pediatrics 137, e20153257 (2016).
pubmed: 26783326 pmcid: 4732362 doi: 10.1542/peds.2015-3257
Ozeki, M. et al. The impact of sirolimus therapy on lesion size, clinical symptoms, and quality of life of patients with lymphatic anomalies. Orphanet J. Rare Dis. 14, 141 (2019).
pubmed: 31196128 pmcid: 6567608 doi: 10.1186/s13023-019-1118-1
Triana, P. et al. Sirolimus in the treatment of vascular anomalies. Eur. J. Pediatr. Surg. 27, 86–90 (2017).
pubmed: 27723921
Venot, Q. et al. Targeted therapy in patients with PIK3CA-related overgrowth syndrome. Nature 558, 540–546 (2018).
pubmed: 29899452 pmcid: 7610773 doi: 10.1038/s41586-018-0217-9
Wang, Y. et al. Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis. Nature 465, 483-486 (2010).
pubmed: 20445537 doi: 10.1038/nature09002
Ridder, D. A. et al. TAK1 in brain endothelial cells mediates fever and lethargy. J. Exp. Med. 208, 2615–2623 (2011).
pubmed: 22143887 pmcid: 3244031 doi: 10.1084/jem.20110398
Claxton, S. et al. Efficient, inducible Cre-recombinase activation in vascular endothelium. Genesis 46, 74–80 (2008).
pubmed: 18257043 doi: 10.1002/dvg.20367
Chan, A. C. et al. Mutations in 2 distinct genetic pathways result in cerebral cavernous malformations in mice. J. Clin. Invest. 121, 1871–1881 (2011).
pubmed: 21490399 pmcid: 3083782 doi: 10.1172/JCI44393
Foster, K. W. et al. Induction of KLF4 in basal keratinocytes blocks the proliferation-differentiation switch and initiates squamous epithelial dysplasia. Oncogene 24, 1491–1500 (2005).
pubmed: 15674344 pmcid: 1361530 doi: 10.1038/sj.onc.1208307
Trotman, L. C. et al. Pten dose dictates cancer progression in the prostate. PLoS Biol. 1, E59 (2003).
pubmed: 14691534 pmcid: 270016 doi: 10.1371/journal.pbio.0000059
Adams, J. R. et al. Cooperation between Pik3ca and p53 mutations in mouse mammary tumor formation. Cancer Res. 71, 2706–2717 (2011).
pubmed: 21324922 doi: 10.1158/0008-5472.CAN-10-0738
Körbelin, J. et al. A brain microvasculature endothelial cell-specific viral vector with the potential to treat neurovascular and neurological diseases. EMBO Mol. Med. 8, 609–625 (2016).
pubmed: 27137490 pmcid: 4888852 doi: 10.15252/emmm.201506078
Hurst, C. D., Zuiverloon, T. C., Hafner, C., Zwarthoff, E. C. & Knowles, M. A. A SNaPshot assay for the rapid and simple detection of four common hotspot codon mutations in the PIK3CA gene. BMC Res. Notes 2, 66 (2009).
pubmed: 19402901 pmcid: 2683860 doi: 10.1186/1756-0500-2-66
Martelotto, L. G. ‘Frankenstein’ protocol for nuclei isolation from fresh and frozen tissue for snRNAseq. protocols.io https://doi.org/10.17504/protocols.io.3fkgjkw (2020).

Auteurs

Aileen A Ren (AA)

Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA.
ORCID: 0000-0002-1116-900X

Daniel A Snellings (DA)

Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA.
ORCID: 0000-0003-0615-9111

Yourong S Su (YS)

Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, USA.

Courtney C Hong (CC)

Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA.
ORCID: 0000-0003-0515-6816

Marco Castro (M)

Angiogenesis and Metabolism Laboratory, Max Planck institute for Heart and Lung Research, Bad Nauheim, Germany.
ORCID: 0000-0001-7851-7446

Alan T Tang (AT)

Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA.
ORCID: 0000-0003-1422-0349

Matthew R Detter (MR)

Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA.
ORCID: 0000-0003-1207-2565

Nicholas Hobson (N)

Neurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.

Romuald Girard (R)

Neurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.
ORCID: 0000-0002-5893-9315

Sharbel Romanos (S)

Neurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.

Rhonda Lightle (R)

Neurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.

Thomas Moore (T)

Neurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.

Robert Shenkar (R)

Neurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.
ORCID: 0000-0002-1300-6845

Christian Benavides (C)

Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA.

M Makenzie Beaman (MM)

Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA.
ORCID: 0000-0003-4066-2060

Helge Müller-Fielitz (H)

Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism, University of Lübeck, Lübeck, Germany.
ORCID: 0000-0003-2815-4426

Mei Chen (M)

Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA.

Patricia Mericko (P)

Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA.

Jisheng Yang (J)

Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA.

Derek C Sung (DC)

Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA.
ORCID: 0000-0001-6966-2596

Michael T Lawton (MT)

Department of Neurosurgery, The Barrow Neurological Institute, Phoenix, AZ, USA.

J Michael Ruppert (JM)

Cancer Institute, West Virginia University, Morgantown, WV, USA.

Markus Schwaninger (M)

Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism, University of Lübeck, Lübeck, Germany.
ORCID: 0000-0002-4510-9718

Jakob Körbelin (J)

University Medical Center Hamburg-Eppendorf, Department of Oncology, Hematology and Bone Marrow Transplantation, Hamburg, Germany.
ORCID: 0000-0002-5435-7182

Michael Potente (M)

Angiogenesis and Metabolism Laboratory, Max Planck institute for Heart and Lung Research, Bad Nauheim, Germany.
Berlin Institute of Health (BIH) and Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany.
ORCID: 0000-0002-5689-0036

Issam A Awad (IA)

Neurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.

Douglas A Marchuk (DA)

Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA. douglas.marchuk@duke.edu.
ORCID: 0000-0002-3110-6671

Mark L Kahn (ML)

Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA. markkahn@pennmedicine.upenn.edu.
ORCID: 0000-0002-6489-7086

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › PIK3CA and CCM mutations fuel cavernomas...
questionsmedicales.fr › Eucaryotes › Animaux › Groupes animaux › Animaux nouveau-nés › PIK3CA and CCM mutations fuel cavernomas...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Phosphatidylinositol 3-kinases › Phosphatidylinositol-4-phosphate 3-kinase › Phosphatidylinositol 3-kinases de classe I › PIK3CA and CCM mutations fuel cavernomas...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › PIK3CA and CCM mutations fuel cavernomas...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules endothéliales › PIK3CA and CCM mutations fuel cavernomas...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Mutation gain de fonction › PIK3CA and CCM mutations fuel cavernomas...
questionsmedicales.fr › Malformations et maladies congénitales, héréditaires et néonatales › Malformations › Malformations du système nerveux › Malformations vasculaires du système nerveux central › Hémangiome caverneux du système nerveux central › PIK3CA and CCM mutations fuel cavernomas...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › PIK3CA and CCM mutations fuel cavernomas...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription Krüppel-like › Facteur-4 de type Kruppel › PIK3CA and CCM mutations fuel cavernomas...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription Krüppel-like › PIK3CA and CCM mutations fuel cavernomas...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Mutation perte de fonction › PIK3CA and CCM mutations fuel cavernomas...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › MAP Kinase Kinase Kinases › MAP Kinase Kinase Kinase 3 › PIK3CA and CCM mutations fuel cavernomas...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Sérine-thréonine kinases TOR › Complexe-1 cible mécanistique de la rapamycine › PIK3CA and CCM mutations fuel cavernomas...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › PIK3CA and CCM mutations fuel cavernomas...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › PIK3CA and CCM mutations fuel cavernomas...
questionsmedicales.fr › Tumeurs › PIK3CA and CCM mutations fuel cavernomas...
questionsmedicales.fr › Composés chimiques organiques › Lactones › Sirolimus › PIK3CA and CCM mutations fuel cavernomas...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Sérine-thréonine kinases TOR › PIK3CA and CCM mutations fuel cavernomas...