Stepwise release of Activin-A from its inhibitory prodomain is modulated by cysteines and requires furin coexpression to promote melanoma growth.
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
24 Oct 2024
24 Oct 2024
Historique:
received:
15
04
2024
accepted:
11
10
2024
medline:
25
10
2024
pubmed:
25
10
2024
entrez:
25
10
2024
Statut:
epublish
Résumé
The Activin-A precursor dimer can be cleaved by furin, but how this proteolytic maturation is regulated in vivo and how it facilitates access to signaling receptors is unclear. Here, analysis in a syngeneic melanoma grafting model shows that without furin coexpression, Activin-A failed to accelerate tumor growth, correlating with failure of one or both subunits to undergo cleavage in signal-sending cells, even though compensatory processing by host cells nonetheless sustained elevated circulating Activin-A levels. In reporter assays, furin-independent cleavage of one subunit enabled juxtacrine Activin-A signaling, whereas completion of proteolytic maturation by coexpressed furin or by recipient cells stimulated contact-independent activity, crosstalk with BMP receptors, and signal inhibition by follistatin. Mechanistically, Activin-A processing was modulated by allosteric disulfide bonds flanking the furin site. Disruption of these disulfide linkages with the prodomain enabled Activin-A binding to cognate type II receptors independently of proteolytic maturation. Stepwise proteolytic maturation is a novel mechanism to control Activin-A protein interactions and signaling.
Identifiants
pubmed: 39448726
doi: 10.1038/s42003-024-07053-0
pii: 10.1038/s42003-024-07053-0
doi:
Substances chimiques
Activins
104625-48-1
Furin
EC 3.4.21.75
activin A
0
Cysteine
K848JZ4886
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1383Informations de copyright
© 2024. The Author(s).
Références
Ling, N. et al. Pituitary FSH is released by a heterodimer of the β-subunits from the two forms of inhibin. Nature 321, 779–782 (1986).
pubmed: 3086749
doi: 10.1038/321779a0
Thompson, T. B., Cook, R. W., Chapman, S. C., Jardetzky, T. S. & Woodruff, T. K. Beta A versus beta B: is it merely a matter of expression? Mol. Cell. Endocrinol. 225, 9–17 (2004).
pubmed: 15451562
doi: 10.1016/j.mce.2004.02.007
Namwanje, M. & Brown, C. W. Activins and inhibins: roles in development, physiology, and disease. Cold Spring Harb. Perspect. Biol. 8, a021881 (2016).
Aykul, S. & Martinez-Hackert, E. Transforming growth factor-β family ligands can function as antagonists by competing for type II receptor binding. J. Biol. Chem. 291, 10792–10804 (2016).
pubmed: 26961869
pmcid: 4865925
doi: 10.1074/jbc.M115.713487
Aykul, S. et al. Activin A forms a non-signaling complex with ACVR1 and type II Activin/BMP receptors via its finger 2 tip loop. eLife 9, 1–19 (2020).
doi: 10.7554/eLife.54582
Thompson, T. B., Lerch, T. F., Cook, R. W., Woodruff, T. K. & Jardetzky, T. S. The structure of the follistatin: activin complex reveals antagonism of both type I and type II receptor binding. Dev. Cell 9, 535–543 (2005).
pubmed: 16198295
doi: 10.1016/j.devcel.2005.09.008
Loumaye, A. et al. Role of activin A and myostatin in human cancer cachexia. J. Clin. Endocrinol. Metab. 100, 2030–2038 (2015).
pubmed: 25751105
doi: 10.1210/jc.2014-4318
Coerver, K. A. et al. Activin signaling through Activin receptor type II causes the cachexia-like symptoms in Inhibin-deficient mice. Mol. Endocrinol. 10, 534–543 (1996).
pubmed: 8732684
Matzuk, M. M. et al. Development of cancer cachexia-like syndrome and adrenal tumors in inhibin-deficient mice. Proc. Natl Acad. Sci. USA 91, 8817–8821 (1994).
pubmed: 8090730
pmcid: 44697
doi: 10.1073/pnas.91.19.8817
Bloise, E. et al. Activin A in mammalian physiology. Physiol. Rev. 99, 739–780 (2019).
pubmed: 30540228
doi: 10.1152/physrev.00002.2018
Morianos, I., Papadopoulou, G., Semitekolou, M. & Xanthou, G. Activin-A in the regulation of immunity in health and disease. J. Autoimmun. 104, 102314 (2019).
pubmed: 31416681
doi: 10.1016/j.jaut.2019.102314
Ries, A. et al. Activin A: an emerging target for improving cancer treatment? Expert Opin. Ther. Targets 24, 985–996 (2020).
pubmed: 32700590
doi: 10.1080/14728222.2020.1799350
Stove, C. et al. Melanoma cells secrete follistatin, an antagonist of activin-mediated growth inhibition. Oncogene 23, 5330–5339 (2004).
pubmed: 15064726
doi: 10.1038/sj.onc.1207699
Murakami, M., Suzuki, M., Nishino, Y. & Funaba, M. Regulatory expression of genes related to metastasis by TGF-beta and activin A in B16 murine melanoma cells. Mol. Biol. Rep. 37, 1279–1286 (2010).
pubmed: 19288218
doi: 10.1007/s11033-009-9502-x
Donovan, P. et al. Paracrine Activin-A signaling promotes melanoma growth and metastasis through immune evasion. J. Investig. Dermatol. 137, 2578–2587 (2017).
pubmed: 28844941
doi: 10.1016/j.jid.2017.07.845
Lonardo, E. et al. Nodal/activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy. Cell Stem Cell 9, 433–446 (2011).
pubmed: 22056140
doi: 10.1016/j.stem.2011.10.001
Bashir, M., Damineni, S., Mukherjee, G. & Kondaiah, P. Activin-A signaling promotes epithelial–mesenchymal transition, invasion, and metastatic growth of breast cancer. Npj Breast Cancer 1, 15007 (2015).
pubmed: 28721365
pmcid: 5515205
doi: 10.1038/npjbcancer.2015.7
Taylor, C. et al. Activin a signaling regulates cell invasion and proliferation in esophageal adenocarcinoma. Oncotarget 6, 34228–34244 (2015).
pubmed: 26447543
pmcid: 4741448
doi: 10.18632/oncotarget.5349
Yi, Y., Cheng, J.-C., Klausen, C. & Leung, P. C. K. Activin A promotes ovarian cancer cell migration by suppressing E-cadherin expression. Exp. Cell Res. 382, 111471 (2019).
pubmed: 31229504
doi: 10.1016/j.yexcr.2019.06.016
Paajanen, J. et al. Elevated circulating activin A levels in patients with malignant pleural mesothelioma are related to cancer cachexia and reduced response to platinum-based chemotherapy. Clin. Lung Cancer 21, e142–e150 (2020).
pubmed: 31734071
doi: 10.1016/j.cllc.2019.10.013
Seder, C. W. et al. INHBA overexpression promotes cell proliferation and may be epigenetically regulated in esophageal adenocarcinoma. J. Thorac. Oncol. 4, 455–462 (2009).
pubmed: 19240652
doi: 10.1097/JTO.0b013e31819c791a
Pinjusic, K. et al. Activin-A impairs CD8 T cell-mediated immunity and immune checkpoint therapy response in melanoma. J. Immunother. Cancer 10, e004533 (2022).
pubmed: 35580932
pmcid: 9125758
doi: 10.1136/jitc-2022-004533
Ni, X. et al. YAP is essential for Treg-mediated suppression of antitumor immunity. Cancer Discov. 8, 1026–1043 (2018).
pubmed: 29907586
pmcid: 6481611
doi: 10.1158/2159-8290.CD-17-1124
Gutiérrez-Seijo, A. et al. Activin A sustains the metastatic phenotype of tumor-associated macrophages and is a prognostic marker in human cutaneous melanoma. J. Investig. Dermatol. 142, 653–661.e2 (2022).
pubmed: 34499901
doi: 10.1016/j.jid.2021.07.179
Schwall, R. H., Nikolics, K., Szonyi, E., Gorman, C. & Mason, A. J. Recombinant expression and characterization of human activin A. Mol. Endocrinol. 2, 1237–1242 (1988).
pubmed: 3216863
doi: 10.1210/mend-2-12-1237
Huylebroeck, D. et al. Expression and processing of the Activin-A erythroid differentiation factor precursor-a member of the transforming growth factor-beta superfamily. Mol. Endocrinol. 4, 1153–1165 (1990).
pubmed: 1963471
doi: 10.1210/mend-4-8-1153
Mason, A. J., Farnworth, P. G. & Sullivan, J. Characterization and determination of the biological activities of noncleavable high molecular weight forms of inhibin A and activin A. Mol. Endocrinol. 10, 1055–1065 (1996).
pubmed: 8885240
Gray, A. M. & Mason, A. J. Requirement for activin A and transforming growth factor-beta 1 pro-regions in homodimer assembly. Science 247, 1328–1330 (1990).
pubmed: 2315700
doi: 10.1126/science.2315700
Mason, A. J. Functional analysis of the cysteine residues of activin A. Mol. Endocrinol. Baltim. Md 8, 325–332 (1994).
Hinck, A. P., Mueller, T. D. & Springer, T. A. Structural biology and evolution of the TGF-β family. Cold Spring Harb. Perspect. Biol. 8, a022103 (2016).
pubmed: 27638177
pmcid: 5131774
doi: 10.1101/cshperspect.a022103
Seidah, N. G. & Prat, A. The biology and therapeutic targeting of the proprotein convertases. Nat. Rev. Drug Discov. 11, 367–383 (2012).
pubmed: 22679642
doi: 10.1038/nrd3699
Ginefra, P., Filippi, B. G. H., Donovan, P., Bessonnard, S. & Constam, D. B. Compartment-specific biosensors reveal a complementary subcellular distribution of bioactive furin and PC7. Cell Rep. 22, 2176–2189 (2018).
pubmed: 29466742
doi: 10.1016/j.celrep.2018.02.005
Thomas, G. Furin at the cutting edge: From protein traffic to embryogenesis and disease. Nat. Rev. Mol. Cell Biol. 3, 753–766 (2002).
pubmed: 12360192
pmcid: 1964754
doi: 10.1038/nrm934
Blanchet, M. H. et al. Cripto recruits Furin and PACE4 and controls Nodal trafficking during proteolytic maturation. EMBO J. 27, 2580–2591 (2008).
pubmed: 18772886
pmcid: 2567404
doi: 10.1038/emboj.2008.174
Garten, W. et al. Processing of viral glycoproteins by the subtilisin-like endoprotease furin and its inhibition by specific peptidylchloroalkylketones. Biochimie 76, 217–225 (1994).
pubmed: 7819326
doi: 10.1016/0300-9084(94)90149-X
Fuerer, C., Nostro, M. C. & Constam, D. B. Nodal.Gdf1 heterodimers with bound prodomains enable serum-independent Nodal signaling and endoderm differentiation. J. Biol. Chem. 289, 17854–17871 (2014).
pubmed: 24798330
pmcid: 4067217
doi: 10.1074/jbc.M114.550301
Mori, K. et al. Subtilisin-like proprotein convertases, PACE4 and PC8, as well as furin, are endogenous proalbumin convertases in HepG2 cells. J. Biochem. 125, 627–633 (1999).
Jean, F. et al. α1-Antitrypsin Portland, a bioengineered serpin highly selective for furin: application as an antipathogenic agent. Proc. Natl Acad. Sci. USA 95, 7293–7298 (1998).
pubmed: 9636142
pmcid: 22594
doi: 10.1073/pnas.95.13.7293
Wang, X., Fischer, G. & Hyvönen, M. Structure and activation of pro-activin A. Nat. Commun. 7, 12052 (2016).
Li, X. et al. Label-free optofluidic nanobiosensor enables real-time analysis of single-cell cytokine secretion. Small 14, 1800698 (2018).
doi: 10.1002/smll.201800698
Ansaryan, S. et al. High-throughput spatiotemporal monitoring of single-cell secretions via plasmonic microwell arrays. Nat. Biomed. Eng. 7, 943–958 (2023).
pubmed: 37012313
pmcid: 10365996
doi: 10.1038/s41551-023-01017-1
Chiu, J. & Hogg, P. J. Allosteric disulfides: Sophisticated molecular structures enabling flexible protein regulation. J. Biol. Chem. 294, 2949–2960 (2019).
pubmed: 30635401
pmcid: 6393624
doi: 10.1074/jbc.REV118.005604
Lu, J. & Holmgren, A. The thioredoxin superfamily in oxidative protein folding. Antioxid. Redox Signal. 21, 457–470 (2014).
pubmed: 24483600
doi: 10.1089/ars.2014.5849
Olsen, O. E. et al. Activin A inhibits BMP-signaling by binding ACVR2A and ACVR2B. Cell Commun. Signal. 13, 27 (2015).
pubmed: 26047946
pmcid: 4467681
doi: 10.1186/s12964-015-0104-z
Rejon, C. A. et al. Activins bind and signal via bone morphogenetic protein receptor type II (BMPR2) in immortalized gonadotrope-like cells. Cell. Signal. 25, 2717–2726 (2013).
pubmed: 24018044
doi: 10.1016/j.cellsig.2013.09.002
Gentry, L. E., Lioubin, M. N., Purchio, A. F. & Marquardt, H. Molecular events in the processing of recombinant type 1 pre-pro-transforming growth factor beta to the mature polypeptide. Mol. Cell. Biol. 8, 4162–4168 (1988).
pubmed: 3185545
pmcid: 365485
Brunner, A. M., Marquardt, H., Malacko, A. R., Lioubin, M. N. & Purchio, A. F. Site-directed mutagenesis of cysteine residues in the pro region of the transforming growth factor beta 1 precursor. Expression and characterization of mutant proteins. J. Biol. Chem. 264, 13660–13664 (1989).
pubmed: 2474534
doi: 10.1016/S0021-9258(18)80047-3
Todorovic, V. & Rifkin, D. B. LTBPs, more than just an escort service. J. Cell. Biochem. 113, 410–418 (2012).
pubmed: 22223425
pmcid: 3254144
doi: 10.1002/jcb.23385
Constam, D. B. Regulation of TGFβ and related signals by precursor processing. Semin. Cell Dev. Biol. 32, 85–97 (2014).
pubmed: 24508081
doi: 10.1016/j.semcdb.2014.01.008
Saharinen, J. & Keski-Oja, J. Specific sequence motif of 8-Cys repeats of TGF-beta binding proteins, LTBPs, creates a hydrophobic interaction surface for binding of small latent TGF-beta. Mol. Biol. Cell 11, 2691–2704 (2000).
pubmed: 10930463
pmcid: 14949
doi: 10.1091/mbc.11.8.2691
Eklund, H., Gleason, F. K. & Holmgren, A. Structural and functional relations among thioredoxins of different species. Proteins Struct. Funct. Bioinform. 11, 13–28 (1991).
doi: 10.1002/prot.340110103
Gromer, S., Urig, S. & Becker, K. The thioredoxin system - from science to clinic. Med. Res. Rev. 24, 40–89 (2004).
pubmed: 14595672
doi: 10.1002/med.10051
Quan, S., Schneider, I., Pan, J., Von Hacht, A. & Bardwell, J. C. A. The CXXC motif is more than a redox rheostat. J. Biol. Chem. 282, 28823–28833 (2007).
pubmed: 17675287
doi: 10.1074/jbc.M705291200
Yoshinaga, K. et al. Perturbation of transforming growth factor (TGF)-beta1 association with latent TGF-beta binding protein yields inflammation and tumors. Proc. Natl Acad. Sci. USA 105, 18758–18763 (2008).
pubmed: 19022904
pmcid: 2596235
doi: 10.1073/pnas.0805411105
Constam, D. B. Running the gauntlet: an overview of the modalities of travel employed by the putative morphogen Nodal. Curr. Opin. Genet. Dev. 19, 302–307 (2009).
pubmed: 19631522
doi: 10.1016/j.gde.2009.06.006
Walton, K. L. et al. A common biosynthetic pathway governs the dimerization and secretion of inhibin and related transforming growth factor β (TGFβ) ligands. J. Biol. Chem. 284, 9311–9320 (2009).
pubmed: 19193648
pmcid: 2666583
doi: 10.1074/jbc.M808763200
Chen, J. L. et al. Development of novel activin-targeted therapeutics. Mol. Ther. 23, 434–444 (2015).
pubmed: 25399825
doi: 10.1038/mt.2014.221
Johnson, K. E. et al. Biological activity and in vivo half-life of pro-activin A in male rats. Mol. Cell. Endocrinol. 422, 84–92 (2016).
pubmed: 26687063
doi: 10.1016/j.mce.2015.12.007
Munger, J. S. et al. The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 96, 319–328 (1999).
pubmed: 10025398
doi: 10.1016/S0092-8674(00)80545-0
Mu, D. et al. The integrin alpha(v)beta8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-beta1. J. Cell Biol. 157, 493–507 (2002).
pubmed: 11970960
pmcid: 2173277
doi: 10.1083/jcb.200109100
Dong, X. et al. Force interacts with macromolecular structure in activation of TGF-β. Nature 542, 55–59 (2017).
pubmed: 28117447
pmcid: 5586147
doi: 10.1038/nature21035
Mesnard, D., Donnison, M., Fuerer, C., Pfeffer, P. L. & Constam, D. B. The microenvironment patterns the pluripotent mouse epiblast through paracrine furin and Pace4 proteolytic activities. Genes Dev. 25, 1871–1880 (2011).
pubmed: 21896659
pmcid: 3175722
doi: 10.1101/gad.16738711
Beck, S. et al. Extraembryonic proteases regulate Nodal signalling during gastrulation. Nat. Cell Biol. 4, 981–985 (2002).
pubmed: 12447384
doi: 10.1038/ncb890
He, Z., Khatib, A. M. & Creemers, J. W. M. The proprotein convertase furin in cancer: more than an oncogene. Oncogene 41, 1252–1262 (2022).
pubmed: 34997216
doi: 10.1038/s41388-021-02175-9
Siegfried, G., Descarpentrie, J., Evrard, S. & Khatib, A. M. Proprotein convertases: Key players in inflammation-related malignancies and metastasis. Cancer Lett. 473, 50–61 (2020).
pubmed: 31899298
doi: 10.1016/j.canlet.2019.12.027
Kondás, K., Szláma, G., Trexler, M. & Patthy, L. Both WFIKKN1 and WFIKKN2 have high affinity for growth and differentiation factors 8 and 11. J. Biol. Chem. 283, 23677–23684 (2008).
pubmed: 18596030
pmcid: 3259755
doi: 10.1074/jbc.M803025200
Li, S. et al. Activin A binds to perlecan through its pro-region that has heparin/heparan sulfate binding activity. J. Biol. Chem. 285, 36645–36655 (2010).
pubmed: 20843788
pmcid: 2978593
doi: 10.1074/jbc.M110.177865
Hampf, M. & Gossen, M. A protocol for combined Photinus and Renilla luciferase quantification compatible with protein assays. Anal. Biochem. 356, 94–99 (2006).
pubmed: 16750160
doi: 10.1016/j.ab.2006.04.046
Logeart-Avramoglou, D., Bourguignon, M., Oudina, K., Ten Dijke, P. & Petite, H. An assay for the determination of biologically active bone morphogenetic proteins using cells transfected with an inhibitor of differentiation promoter-luciferase construct. Anal. Biochem. 349, 78–86 (2006).
pubmed: 16307714
doi: 10.1016/j.ab.2005.10.030
Rappsilber, J., Mann, M. & Ishihama, Y. Protocol for micro-purification, enrichment, pre-fractionation and storage of peptides for proteomics using StageTips. Nat. Protoc. 2, 1896–1906 (2007).
pubmed: 17703201
doi: 10.1038/nprot.2007.261
Feldman, J. P. & Goldwasser, R. A mathematical model for tumor volume evaluation using two-dimensions. J. Appl. Quant. Methods 4, 455–462 (2009).
Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold. Nature 596, 583–589 (2021).
pubmed: 34265844
pmcid: 8371605
doi: 10.1038/s41586-021-03819-2
Ramachandran, S., Kota, P., Ding, F. & Dokholyan, N. V. Automated minimization of steric clashes in protein structures. Proteins Struct. Funct. Bioinform. 79, 261–270 (2011).
doi: 10.1002/prot.22879
Goebel, E. J. et al. Structural characterization of an activin class ternary receptor complex reveals a third paradigm for receptor specificity. Proc. Natl Acad. Sci. USA 116, 15505–15513 (2019).
pubmed: 31315975
pmcid: 6681762
doi: 10.1073/pnas.1906253116