Small-molecule inhibition of Lats kinases may promote Yap-dependent proliferation in postmitotic mammalian tissues.

Adaptor Proteins, Signal Transducing / genetics Animals Cell Line Cell Line, Tumor Cell Proliferation / drug effects Ependymoglial Cells / cytology HEK293 Cells Hair Cells, Auditory, Inner / cytology Humans Mice, Knockout Mice, Transgenic Myocytes, Cardiac / cytology Protein Serine-Threonine Kinases / antagonists & inhibitors Signal Transduction / drug effects Small Molecule Libraries / pharmacology Tumor Suppressor Proteins / antagonists & inhibitors YAP-Signaling Proteins

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
25 05 2021
Historique:
received: 24 03 2020
accepted: 20 04 2021
entrez: 26 5 2021
pubmed: 27 5 2021
medline: 16 6 2021
Statut: epublish

Résumé

Hippo signaling is an evolutionarily conserved pathway that restricts growth and regeneration predominantly by suppressing the activity of the transcriptional coactivator Yap. Using a high-throughput phenotypic screen, we identified a potent and non-toxic activator of Yap. In vitro kinase assays show that the compound acts as an ATP-competitive inhibitor of Lats kinases-the core enzymes in Hippo signaling. The substance prevents Yap phosphorylation and induces proliferation of supporting cells in the murine inner ear, murine cardiomyocytes, and human Müller glia in retinal organoids. RNA sequencing indicates that the inhibitor reversibly activates the expression of transcriptional Yap targets: upon withdrawal, a subset of supporting-cell progeny exits the cell cycle and upregulates genes characteristic of sensory hair cells. Our results suggest that the pharmacological inhibition of Lats kinases may promote initial stages of the proliferative regeneration of hair cells, a process thought to be permanently suppressed in the adult mammalian inner ear.

Identifiants

DOI: 10.1038/s41467-021-23395-3 PMID: 34035288 PMC: PMC8149661
pubmed: 34035288
doi: 10.1038/s41467-021-23395-3
pii: 10.1038/s41467-021-23395-3
pmc: PMC8149661
doi:

Substances chimiques

Adaptor Proteins, Signal Transducing 0
Small Molecule Libraries 0
Tumor Suppressor Proteins 0
YAP-Signaling Proteins 0
Yap1 protein, mouse 0
LATS1 protein, human EC 2.7.1.-
LATS2 protein, human EC 2.7.1.11
Protein Serine-Threonine Kinases EC 2.7.11.1

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

3100

Subventions

Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NIDCD NIH HHS
ID : R01 DC015829
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007739
Pays : United States
Organisme : NIDCD NIH HHS
ID : R01 DC015530
Pays : United States
Organisme : NIDCD NIH HHS
ID : R21 DC016984
Pays : United States

Références

Moya, I. M. & Halder, G. Hippo-YAP/TAZ signalling in organ regeneration and regenerative medicine. Nat. Rev. Mol. Cell Biol. 20, 211–226 (2019).
pubmed: 30546055 doi: 10.1038/s41580-018-0086-y
Silver, J., Schwab, M. E. & Popovich, P. G. Central nervous system regenerative failure: role of oligodendrocytes, astrocytes, and microglia. Cold Spring Harb. Perspect. Biol. 7, a020602 (2015).
pmcid: 4355267 doi: 10.1101/cshperspect.a020602
Hashimoto, H., Olson, E. N. & Bassel-Duby, R. Therapeutic approaches for cardiac regeneration and repair. Nat. Rev. Cardiol. 15, 585–600 (2018).
pubmed: 29872165 pmcid: 6241533 doi: 10.1038/s41569-018-0036-6
Burns, J. C. & Stone, J. S. Development and regeneration of vestibular hair cells in mammals. Semin. Cell Dev. Biol. 65, 96–105 (2017).
pubmed: 27864084 doi: 10.1016/j.semcdb.2016.11.001
Groves, A. K. The challenge of hair cell regeneration. Exp. Biol. Med. 235, 434–446 (2010).
doi: 10.1258/ebm.2009.009281
Scheibinger, M., Ellwanger, D. C., Corrales, C. E., Stone, J. S. & Heller, S. Aminoglycoside damage and hair cell regeneration in the chicken utricle. J. Assoc. Res. Otolaryngol. 19, 17–29 (2018).
pubmed: 29134476 doi: 10.1007/s10162-017-0646-4
Kelley, M. W., Talreja, D. R. & Corwin, J. T. Replacement of hair cells after laser microbeam irradiation in cultured organs of corti from embryonic and neonatal mice. J. Neurosci. 15, 3013–3026 (1995).
pubmed: 7722642 pmcid: 6577748 doi: 10.1523/JNEUROSCI.15-04-03013.1995
Golub, J. S. et al. Hair cell replacement in adult mouse utricles after targeted ablation of hair cells with diphtheria toxin. J. Neurosci. 32, 15093–15105 (2012).
pubmed: 23100430 pmcid: 3544304 doi: 10.1523/JNEUROSCI.1709-12.2012
Burns, J. C., Cox, B. C., Thiede, B. R., Zuo, J. & Corwin, J. T. In vivo proliferative regeneration of balance hair cells in newborn mice. J. Neurosci. J. Soc. Neurosci. 32, 6570–6577 (2012).
doi: 10.1523/JNEUROSCI.6274-11.2012
Cox, B. C. et al. Spontaneous hair cell regeneration in the neonatal mouse cochlea in vivo. Development 141, 816–829 (2014).
Johnson, R. & Halder, G. The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment. Nat. Rev. Drug Discov. 13, 63–79 (2013).
pubmed: 24336504 pmcid: 4167640 doi: 10.1038/nrd4161
Meng, Z., Moroishi, T. & Guan, K.-L. Mechanisms of Hippo pathway regulation. Genes Dev. 30, 1–17 (2016).
pubmed: 26728553 pmcid: 4701972 doi: 10.1101/gad.274027.115
Manning, S. A., Kroeger, B. & Harvey, K. F. The regulation of Yorkie, YAP and TAZ: new insights into the Hippo pathway. Development 147, dev179069 (2020).
pubmed: 32341025 doi: 10.1242/dev.179069
Totaro, A., Panciera, T. & Piccolo, S. YAP/TAZ upstream signals and downstream responses. Nat. Cell Biol. 20, 888–899 (2018).
pubmed: 30050119 pmcid: 6186418 doi: 10.1038/s41556-018-0142-z
Morikawa, Y., Heallen, T., Leach, J., Xiao, Y. & Martin, J. F. Dystrophin–glycoprotein complex sequesters Yap to inhibit cardiomyocyte proliferation. Nature 547, 227–231 (2017).
pubmed: 28581498 pmcid: 5528853 doi: 10.1038/nature22979
Bassat, E. et al. The extracellular matrix protein agrin promotes heart regeneration in mice. Nature 547, 179–184 (2017).
pubmed: 28581497 pmcid: 5769930 doi: 10.1038/nature22978
Monroe, T. O. et al. YAP partially reprograms chromatin accessibility to directly induce adult cardiogenesis in vivo. Dev. Cell 48, 765–779 (2019).
pubmed: 30773489 pmcid: 6435425 doi: 10.1016/j.devcel.2019.01.017
Rueda, E. M. et al. The Hippo pathway blocks mammalian retinal Müller glial cell reprogramming. Cell Rep. 27, 1637–1649 (2019).
pubmed: 31067451 pmcid: 6521882 doi: 10.1016/j.celrep.2019.04.047
Fan, F. et al. Pharmacological targeting of kinases MST1 and MST2 augments tissue repair and regeneration. Sci. Transl. Med. 8, 352ra108 (2016).
pubmed: 27535619 doi: 10.1126/scitranslmed.aaf2304
Gnedeva, K., Jacobo, A., Salvi, J. D., Petelski, A. A. & Hudspeth, A. J. Elastic force restricts growth of the murine utricle. eLife 6, e25681 (2017).
Gnedeva, K. et al. Organ of Corti size is governed by Yap/Tead-mediated progenitor self-renewal. Proc. Natl Acad. Sci. USA 117, 13552–13561 (2020).
pubmed: 32482884 doi: 10.1073/pnas.2000175117 pmcid: 7306825
Rudolf, M. A. et al. YAP mediates hair cell regeneration in balance organs of chickens, but LATS kinases suppress its activity in mice. J. Neurosci. 40, 3915–3932 (2020).
pubmed: 32341094 pmcid: 7219294 doi: 10.1523/JNEUROSCI.0306-20.2020
Kim, N.-G., Koh, E., Chen, X. & Gumbiner, B. M. E-cadherin mediates contact inhibition of proliferation through Hippo signaling-pathway components. Proc. Natl Acad. Sci. USA 108, 11930–11935 (2011).
pubmed: 21730131 doi: 10.1073/pnas.1103345108 pmcid: 3141988
Schlegelmilch, K. et al. Yap1 acts downstream of α-catenin to control epidermal proliferation. Cell 144, 782–795 (2011).
pubmed: 21376238 pmcid: 3237196 doi: 10.1016/j.cell.2011.02.031
Zhao, B. et al. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev. 21, 2747–2761 (2007).
pubmed: 17974916 pmcid: 2045129 doi: 10.1101/gad.1602907
Mellado Lagarde, M. M. et al. Spontaneous regeneration of cochlear supporting cells after neonatal ablation ensures hearing in the adult mouse. Proc. Natl Acad. Sci. USA 111, 16919–16924 (2014).
pubmed: 25385613 doi: 10.1073/pnas.1408064111 pmcid: 4250150
Xu, J. et al. Identification of mouse cochlear progenitors that develop hair and supporting cells in the organ of Corti. Nat. Commun. 8, 15046 (2017).
pubmed: 28492243 pmcid: 5437288 doi: 10.1038/ncomms15046
Liu-Chittenden, Y. et al. Genetic and pharmacological disruption of the TEAD–YAP complex suppresses the oncogenic activity of YAP. Genes Dev. 26, 1300–1305 (2012).
pubmed: 22677547 pmcid: 3387657 doi: 10.1101/gad.192856.112
Zhang, N. et al. The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals. Dev. Cell 19, 27–38 (2010).
pubmed: 20643348 pmcid: 2925178 doi: 10.1016/j.devcel.2010.06.015
Arnold, K. et al. Sox2(+) adult stem and progenitor cells are important for tissue regeneration and survival of mice. Cell Stem Cell 9, 317–329 (2011).
pubmed: 21982232 pmcid: 3538360 doi: 10.1016/j.stem.2011.09.001
Huang, W. et al. The N-terminal phosphodegron targets TAZ/WWTR1 protein for SCFβ-TrCP-dependent degradation in response to phosphatidylinositol 3-kinase inhibition. J. Biol. Chem. 287, 26245–26253 (2012).
pubmed: 22692215 pmcid: 3406709 doi: 10.1074/jbc.M112.382036
Mo, J.-S. et al. Cellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathway. Nat. Cell Biol. 17, 500–510 (2015).
pubmed: 25751140 pmcid: 4380774 doi: 10.1038/ncb3111
Hong, A. W. & Guan, K.-L. Non-radioactive LATS in vitro Kinase Assay. Bio-Protocol 7, e2391 (2017).
Moroishi, T. et al. A YAP/TAZ-induced feedback mechanism regulates Hippo pathway homeostasis. Genes Dev. 29, 1271–1284 (2015).
pubmed: 26109050 pmcid: 4495398 doi: 10.1101/gad.262816.115
Pearce, L. R., Komander, D. & Alessi, D. R. The nuts and bolts of AGC protein kinases. Nat. Rev. Mol. Cell Biol. 11, 9–22 (2010).
pubmed: 20027184 doi: 10.1038/nrm2822
Hirozane, Y. et al. Structure-based rational design of staurosporine-based fluorescent probe with broad-ranging kinase affinity for kinase panel application. Bioorg. Med. Chem. Lett. 29, 126641 (2019).
pubmed: 31526603 doi: 10.1016/j.bmcl.2019.126641
Heintz, N. Gene expression nervous system atlas (GENSAT). Nat. Neurosci. 7, 483 (2004).
pubmed: 15114362 doi: 10.1038/nn0504-483
Huang, D. W., Sherman, B. T. & Lempicki, R. A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 4, 44–57 (2009).
doi: 10.1038/nprot.2008.211
Burns, J. C., On, D., Baker, W., Collado, M. S. & Corwin, J. T. Over half the hair cells in the mouse utricle first appear after birth, with significant numbers originating from early postnatal mitotic production in peripheral and striolar growth zones. J. Assoc. Res. Otolaryngol. 13, 609–627 (2012).
pubmed: 22752453 pmcid: 3441952 doi: 10.1007/s10162-012-0337-0
Gnedeva, K. & Hudspeth, A. J. SoxC transcription factors are essential for the development of the inner ear. Proc. Natl Acad. Sci. USA 112, 14066–14071 (2015).
pubmed: 26504244 doi: 10.1073/pnas.1517371112 pmcid: 4653225
Zanconato, F. et al. Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth. Nat. Cell Biol. 17, 1218–1227 (2015).
pubmed: 26258633 pmcid: 6186417 doi: 10.1038/ncb3216
Frade, J. M. & Ovejero-Benito, M. C. Neuronal cell cycle: the neuron itself and its circumstances. Cell Cycle 14, 712–720 (2015).
pubmed: 25590687 pmcid: 4418291 doi: 10.1080/15384101.2015.1004937
Morikawa, Y. et al. Actin cytoskeletal remodeling with protrusion formation is essential for heart regeneration in Hippo-deficient mice. Sci. Signal. 8, ra41 (2015).
pubmed: 25943351 pmcid: 4442128 doi: 10.1126/scisignal.2005781
Yao, K. et al. Restoration of vision after de novo genesis of rod photoreceptors in mammalian retinas. Nature 560, 484–488 (2018).
pubmed: 30111842 pmcid: 6107416 doi: 10.1038/s41586-018-0425-3
Pobbati, A. V. et al. Identification of quinolinols as activators of TEAD-dependent transcription. ACS Chem. Biol. 14, 2909–2921 (2019).
doi: 10.1021/acschembio.9b00786 pubmed: 31742995
Meng, Z. et al. MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway. Nat. Commun. 6, 247 (2015).
doi: 10.1038/ncomms9357
Lee, Y.-S., Liu, F. & Segil, N. A morphogenetic wave of p27Kip1 transcription directs cell cycle exit during organ of Corti development. Dev. Camb. Engl. 133, 2817–2826 (2006).
Chai, R. et al. Wnt signaling induces proliferation of sensory precursors in the postnatal mouse cochlea. Proc. Natl Acad. Sci. USA 109, 8167–8172 (2012).
pubmed: 22562792 doi: 10.1073/pnas.1202774109 pmcid: 3361451
Jacques, B. E. et al. A dual function for canonical Wnt/β-catenin signaling in the developing mammalian cochlea. Dev. Camb. Engl. 139, 4395–4404 (2012).
Shi, F., Hu, L. & Edge, A. S. B. Generation of hair cells in neonatal mice by β-catenin overexpression in Lgr5-positive cochlear progenitors. Proc. Natl Acad. Sci. USA 110, 13851–13856 (2013).
pubmed: 23918377 doi: 10.1073/pnas.1219952110 pmcid: 3752268
Ni, W. et al. Extensive supporting cell proliferation and mitotic hair cell generation by in vivo genetic reprogramming in the neonatal mouse cochlea. J. Neurosci. 36, 8734–8745 (2016).
pubmed: 27535918 pmcid: 6601894 doi: 10.1523/JNEUROSCI.0060-16.2016
Furth, N. & Aylon, Y. The LATS1 and LATS2 tumor suppressors: beyond the Hippo pathway. Cell Death Differ. 24, 1488–1501 (2017).
pubmed: 28644436 pmcid: 5563998 doi: 10.1038/cdd.2017.99
Juan, W. & Hong, W. Targeting the hippo signaling pathway for tissue regeneration and cancer therapy. Genes 7, 55 (2016).
pmcid: 5042386 doi: 10.3390/genes7090055
Moroishi, T. et al. The hippo pathway kinases LATS1/2 suppress cancer immunity. Cell 167, e17 (2016).
doi: 10.1016/j.cell.2016.11.005
Agah, R. et al. Gene recombination in postmitotic cells. Targeted expression of Cre recombinase provokes cardiac-restricted, site-specific rearrangement in adult ventricular muscle in vivo. J. Clin. Investig. 100, 169–179 (1997).
pubmed: 9202069 doi: 10.1172/JCI119509 pmcid: 508177
Madisen, L. et al. A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat. Neurosci. 13, 133–140 (2010).
pubmed: 20023653 doi: 10.1038/nn.2467
Bickerton, G. R., Paolini, G. V., Besnard, J., Muresan, S. & Hopkins, A. L. Quantifying the chemical beauty of drugs. Nat. Chem. 4, 90–98 (2012).
pubmed: 22270643 pmcid: 3524573 doi: 10.1038/nchem.1243
Zhong, X. et al. Generation of three-dimensional retinal tissue with functional photoreceptors from human iPSCs. Nat. Commun. 5, 4047 (2014).
pubmed: 24915161 doi: 10.1038/ncomms5047
Schindelin, J. et al. Fiji: an open-source platform for biological-image analysis. Nat. Methods 9, 676–682 (2012).
doi: 10.1038/nmeth.2019 pubmed: 22743772
Carpenter, A. E. et al. CellProfiler: image analysis software for identifying and quantifying cell phenotypes. Genome Biol. 7, R100 (2006).
pubmed: 17076895 pmcid: 1794559 doi: 10.1186/gb-2006-7-10-r100
Huang, D., Zhou, T., Lafleur, K., Nevado, C. & Caflisch, A. Kinase selectivity potential for inhibitors targeting the ATP binding site: a network analysis. Bioinforma. Oxf. Engl. 26, 198–204 (2010).
doi: 10.1093/bioinformatics/btp650
Bandarage, U. K. et al. ROCK inhibitors 3: Design, synthesis and structure-activity relationships of 7-azaindole-based Rho kinase (ROCK) inhibitors. Bioorg. Med. Chem. Lett. 28, 2622–2626 (2018).
pubmed: 30082069 doi: 10.1016/j.bmcl.2018.06.040
Halgren, T. A. et al. Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J. Med. Chem. 47, 1750–1759 (2004).
pubmed: 15027866 doi: 10.1021/jm030644s
Kannan, N., Haste, N., Taylor, S. S. & Neuwald, A. F. The hallmark of AGC kinase functional divergence is its C-terminal tail, a cis-acting regulatory module. Proc. Natl Acad. Sci. USA 104, 1272–1277 (2007).
pubmed: 17227859 doi: 10.1073/pnas.0610251104 pmcid: 1783090
Burns, J. C., Kelly, M. C., Hoa, M., Morell, R. J. & Kelley, M. W. Single-cell RNA-Seq resolves cellular complexity in sensory organs from the neonatal inner ear. Nat. Commun. 6, 8557 (2015).
pubmed: 26469390 doi: 10.1038/ncomms9557
Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinforma. Oxf. Engl. 29, 15–21 (2013).
doi: 10.1093/bioinformatics/bts635
Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).
pubmed: 25516281 pmcid: 4302049 doi: 10.1186/s13059-014-0550-8
Marini, F. & Binder, H. pcaExplorer: an R/Bioconductor package for interacting with RNA-seq principal components. BMC Bioinforma. 20, 331 (2019).
doi: 10.1186/s12859-019-2879-1

Auteurs

Nathaniel Kastan (N)

Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA.
Laboratory of Sensory Neuroscience, The Rockefeller University, New York, NY, USA.

Ksenia Gnedeva (K)

Tina and Rick Caruso Department of Otolaryngology-Head and Neck Surgery, University of Southern California, Los Angles, CA, USA. gnedeva@usc.edu.
ORCID: 0000-0002-3870-9256

Theresa Alisch (T)

Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA.
Laboratory of Sensory Neuroscience, The Rockefeller University, New York, NY, USA.

Aleksandra A Petelski (AA)

Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA.
Laboratory of Sensory Neuroscience, The Rockefeller University, New York, NY, USA.
Department of Bioengineering and Barnett Institute, Northeastern University, Boston, MA, USA.

David J Huggins (DJ)

Tri-Institutional Therapeutics Discovery Institute, New York, NY, USA.
Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, NY, USA.

Jeanne Chiaravalli (J)

High-Throughput Screening Resource Center, The Rockefeller University, New York, NY, USA.
Institut Pasteur, Paris, France.

Alla Aharanov (A)

Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.

Avraham Shakked (A)

Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.

Eldad Tzahor (E)

Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
ORCID: 0000-0002-5212-9426

Aaron Nagiel (A)

Department of Surgery Children's Hospital Los Angeles, Vision Center, Los Angeles, CA, USA.
Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA.
USC Roski Eye Institute, Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
ORCID: 0000-0001-7275-6980

Neil Segil (N)

Tina and Rick Caruso Department of Otolaryngology-Head and Neck Surgery, University of Southern California, Los Angles, CA, USA.
Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angles, CA, USA.
ORCID: 0000-0002-0441-2067

A J Hudspeth (AJ)

Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA.
Laboratory of Sensory Neuroscience, The Rockefeller University, New York, NY, USA.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines adaptatrices de la transduction du signal › Small-molecule inhibition of Lats kinases may...
questionsmedicales.fr › Eucaryotes › Animaux › Small-molecule inhibition of Lats kinases may...
questionsmedicales.fr › Cellules › Cellules cultivées › Lignée cellulaire › Small-molecule inhibition of Lats kinases may...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Small-molecule inhibition of Lats kinases may...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Croissance › Processus de croissance cellulaire › Prolifération cellulaire › Small-molecule inhibition of Lats kinases may...
questionsmedicales.fr › Cellules › Névroglie › Cellules épendymogliales › Small-molecule inhibition of Lats kinases may...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules HEK293 › Small-molecule inhibition of Lats kinases may...
questionsmedicales.fr › Cellules › Neurones › Neurones afférents › Cellules réceptrices sensorielles › Mécanorécepteurs › Cellules neuroépithéliales › Cellules ciliées auditives › Cellules ciliées auditives internes › Small-molecule inhibition of Lats kinases may...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Small-molecule inhibition of Lats kinases may...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › Souris knockout › Small-molecule inhibition of Lats kinases may...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › Small-molecule inhibition of Lats kinases may...
questionsmedicales.fr › Cellules › Cellules musculaires › Myocytes cardiaques › Small-molecule inhibition of Lats kinases may...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Small-molecule inhibition of Lats kinases may...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Small-molecule inhibition of Lats kinases may...
questionsmedicales.fr › Actions chimiques et utilisations › Utilisations spécialisées de produits chimiques › Produits chimiques de laboratoire › Bibliothèques de petites molécules › Small-molecule inhibition of Lats kinases may...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines suppresseurs de tumeurs › Small-molecule inhibition of Lats kinases may...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines adaptatrices de la transduction du signal › Protéines de signalisation YAP › Small-molecule inhibition of Lats kinases may...