Arl2-GTP and Arl3-GTP regulate a GDI-like transport system for farnesylated cargo
Abstract
Lipidated Rho and Rab GTP-binding proteins are transported between membranes in complex with solubilizing factors called 'guanine nucleotide dissociation inhibitors' (GDIs). Unloading from GDIs using GDI displacement factors (GDFs) has been proposed but remains mechanistically elusive. PDEδ is a putative solubilizing factor for several prenylated Ras-subfamily proteins. Here we report the structure of fully modified farnesylated Rheb-GDP in complex with PDEδ. The structure explains the nucleotide-independent binding of Rheb to PDEδ and the relaxed specificity of PDEδ. We demonstrate that the G proteins Arl2 and Arl3 act in a GTP-dependent manner as allosteric release factors for farnesylated cargo. We thus describe a new transport system for farnesylated G proteins involving a GDI-like molecule and an unequivocal GDF. Considering the importance of PDEδ for proper Ras and Rheb signaling, this study is instrumental in developing a new target for anticancer therapy.
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PDEδ is a protein that binds to KRAS protein and regulates its orientation to membrane compartments.
“PDEδ (phosphodiesterase 6 delta) is a protein that binds to KRAS protein and regulates its orientation to membrane compartments.337,338”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [338]
Cites
ras oncogenes in human cancer: a review.
Bos, J. L. (1989) · PubMed · Cited by 5,061 · see citing works
Kabsch, W. (1993) · Journal of Applied Crystallography · doi:10.1107/s0021889893005588 · Cited by 3,562 · see citing works
Targeting RAS signalling pathways in cancer therapy
Downward, J. (2003) · Nature reviews. Cancer · doi:10.1038/nrc969 · Cited by 3,262 · see citing works
Measurement of co‐localization of objects in dual‐colour confocal images
Manders, E. M. M., Verbeek, F. J., & Aten, J. A. (1993) · Journal of Microscopy · doi:10.1111/j.1365-2818.1993.tb03313.x · Cited by 2,132 · see citing works
GEFs and GAPs: Critical Elements in the Control of Small G Proteins
Bos, J. L., Rehmann, H., & Wittinghofer, A. (2007) · Cell · doi:10.1016/j.cell.2007.05.018 · Cited by 1,903 · see citing works
Self-citationmTORC1-Mediated Cell Proliferation, But Not Cell Growth, Controlled by the 4E-BPs
Dowling, R. J. O., Topisirović, I., Alain, T., Bidinosti, M., Fonseca, B. D., Petroulakis, E., Wang, X., Larsson, O. S., Selvaraj, A., Liu, Y., et al. (2010) · Science · doi:10.1126/science.1187532 · Cited by 726 · see citing works
GDIs: central regulatory molecules in Rho GTPase activation
DerMardirossian, C. M., & Bokoch, G. (2005) · Trends in Cell Biology · doi:10.1016/j.tcb.2005.05.001 · Cited by 680 · see citing works
Rheb promotes cell growth as a component of the insulin/TOR signalling network
Saucedo, L. J., Gao, X., Chiarelli, D. A., Li, L., Pan, D., & Edgar, B. A. (2003) · Nature Cell Biology · doi:10.1038/ncb996 · Cited by 658 · see citing works
Insights into the Mechanism and Catalysis of the Native Chemical Ligation Reaction
Johnson, E. C. B., & Kent, S. B. H. (2006) · Journal of the American Chemical Society · doi:10.1021/ja058344i · Cited by 642 · see citing works
The Small G Proteins of the Arf Family and Their Regulators
Gillingham, A. K., & Munro, S. (2007) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.23.090506.123209 · Cited by 591 · see citing works
Hoffman, G. R., Nassar, N. N., & Cerione, R. A. (2000) · Cell · doi:10.1016/s0092-8674(00)80670-4 · Cited by 505 · see citing works
Legionella pneumophila proteins that regulate Rab1 membrane cycling
Ingmundson, A., Delprato, A., Lambright, D. G., & Roy, C. R. (2007) · Nature · doi:10.1038/nature06336 · Cited by 350 · see citing works
The complex of Arl2‐GTP and PDEδ: from structure to function
Hanzal‐Bayer, M., Renault, L., Roversi, P., Wittinghofer, A., & Hillig, R. C. (2002) · The EMBO Journal · doi:10.1093/emboj/21.9.2095 · Cited by 222 · see citing works
Self-citationIdentification of a GDI displacement factor that releases endosomal Rab GTPases from Rab–GDI
Dirac-Svejstrup, A. B., Sumizawa, T., & Pfeffer, S. R. (1997) · The EMBO Journal · doi:10.1093/emboj/16.3.465 · Cited by 221 · see citing works
A Bifunctional Bacterial Protein Links GDI Displacement to Rab1 Activation
Machner, M. P., & Isberg, R. R. (2007) · Science · doi:10.1126/science.1149121 · Cited by 215 · see citing works
Structure of Rab GDP-Dissociation Inhibitor in Complex with Prenylated YPT1 GTPase
Rak, A., Pylypenko, O., Durek, T., Watzke, A., Kushnir, S., Brunsveld, L., Waldmann, H., Goody, R. S., & Alexandrov, K. A. (2003) · Science · doi:10.1126/science.1087761 · Cited by 213 · see citing works
Self-citationThe Rac-RhoGDI complex and the structural basis for the regulation of Rho proteins by RhoGDI.
Scheffzek, K., Stephan, I., Jensen, O. N., Illenberger, D., & Gierschik, P. (2000) · Nature Structural Biology · doi:10.1038/72392 · Cited by 198 · see citing works
Therapeutic intervention based on protein prenylation and associated modifications
Gelb, M. H., Brunsveld, L., Hrycyna, C. A., Michaelis, S., Tamanoi, F., Voorhis, W. C. V., & Waldmann, H. (2006) · Nature Chemical Biology · doi:10.1038/nchembio818 · Cited by 195 · see citing works
Self-citationThe Rheb family of GTP-binding proteins
Aspuria, P.-J. P., & Tamanoi, F. (2004) · Cellular Signalling · doi:10.1016/j.cellsig.2004.03.019 · Cited by 181 · see citing works
The retinitis pigmentosa 2 gene product is a GTPase-activating protein for Arf-like 3
Veltel, S., Gasper, R., Eisenacher, E., & Wittinghofer, A. (2008) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1396 · Cited by 173 · see citing works
Self-citationGosser, Y. Q., Nomanbhoy, T. K., Aghazadeh, B., Manor, D., Combs, C., Cerione, R. A., & Rosen, M. K. (1997) · Nature · doi:10.1038/42961 · Cited by 170 · see citing works
Schoebel, S., Oesterlin, L. K., Blankenfeldt, W., Goody, R. S., & Itzen, A. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.11.014 · Cited by 161 · see citing works
Zhang, H., Li, S., Doan, T. A., Rieke, F. M., Detwiler, P. B., Frederick, J. M., & Baehr, W. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0701681104 · Cited by 160 · see citing works
The structural and mechanistic basis for recycling of Rab proteins between membrane compartments
Goody, R. S., Rak, A., & Alexandrov, K. A. (2005) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-005-4486-8 · Cited by 149 · see citing works
Farnesyltransferase inhibitors: promises and realities
Cox, A. D. (2002) · Current Opinion in Pharmacology · doi:10.1016/s1471-4892(02)00181-9 · Cited by 141 · see citing works
ADP-Ribosylation Factor-Like 3 Is Involved in Kidney and Photoreceptor Development
Schrick, J. J., Vogel, P., Abuin, A., Hampton, B., & Rice, D. S. (2006) · American Journal Of Pathology · doi:10.2353/ajpath.2006.050941 · Cited by 138 · see citing works
RhoGDIs Revisited: Novel Roles in Rho Regulation
Dransart, E., Olofsson, B., & Cherfils, J. (2005) · Traffic · doi:10.1111/j.1600-0854.2005.00335.x · Cited by 129 · see citing works
Characterization of the Interaction between RhoGDI and Cdc42Hs Using Fluorescence Spectroscopy
Nomanbhoy, T. K., & Cerione, R. A. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.17.10004 · Cited by 127 · see citing works
Photoreceptor cGMP Phosphodiesterase δ Subunit (PDEδ) Functions as a Prenyl-binding Protein
Zhang, H., Liu, X., Zhang, K., Chen, C.-K., Frederick, J. M., Prestwich, G. D., & Baehr, W. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m306559200 · Cited by 126 · see citing works
Nancy, V., Callebaut, I., Marjou, A. E., & de Gunzburg, J. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m109983200 · Cited by 124 · see citing works
Membrane targeting mechanism of Rab GTPases elucidated by semisynthetic protein probes
Wu, Y., Oesterlin, L. K., Tan, K., Waldmann, H., Alexandrov, K. A., & Goody, R. S. (2010) · Nature Chemical Biology · doi:10.1038/nchembio.386 · Cited by 118 · see citing works
Self-citationNardella, C., Chen, Z., Salmena, L., Carracedo, A., Alimonti, A., Egia, A., Carver, B. S., Gerald, W. L., Cordon‐Cardo, C., & Pandolfi, P. P. (2008) · Genes & Development · doi:10.1101/gad.1699608 · Cited by 117 · see citing works
Tumorigenic activity and therapeutic inhibition of Rheb GTPasePreprint
Mavrakis, K. J., Zhu, H., Silva, R. L. A., Mills, J. R., Teruya‐Feldstein, J., Lowe, S. W., Tam, W., Pelletier, J., & Wendel, H. (2008) · Genes & Development · doi:10.1101/gad.1690808 · Cited by 113 · see citing works
Linari, M., Hanzal‐Bayer, M., & Becker, J. D. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)01117-5 · Cited by 94 · see citing works
Lu, Z. H., Shvartsman, M. B., Lee, A. Y., Shao, J. M., Murray, M. M., Kladney, R. D., Fan, D., Krajewski, S., Chiang, G. G., Mills, G. B., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-3467 · Cited by 92 · see citing works
Florio, S. K., Prusti, R. K., & Beavo, J. A. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.39.24036 · Cited by 91 · see citing works
Structural Basis for the Unique Biological Function of Small GTPase RHEB
Yu, Y., Li, S., Xu, X., Li, Y., Guan, K., Arnold, E., & Ding, J. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m501253200 · Cited by 89 · see citing works
ELMOD2 Is an Arl2 GTPase-activating Protein That Also Acts on Arfs
Bowzard, J. B., Cheng, D., Peng, J., & Kahn, R. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m701347200 · Cited by 78 · see citing works
Synthesis of the Rheb and K‐Ras4B GTPases
Chen, Y., Koch, S., Uhlenbrock, K., Weise, K., Das, D., Gremer, L., Brunsveld, L., Wittinghofer, A., Winter, R., Triola, G., et al. (2010) · Angewandte Chemie International Edition · doi:10.1002/anie.201001884 · Cited by 76 · see citing works
Self-citationSpecificity of Arl2/Arl3 signaling is mediated by a ternary Arl3‐effector‐GAP complex
Veltel, S., Kravchenko, A., Ismail, S., & Wittinghofer, A. (2008) · FEBS Letters · doi:10.1016/j.febslet.2008.05.053 · Cited by 74 · see citing works
Self-citationConsequences of weak interaction of rho GDI with the GTP-bound forms of rho p21 and rac p21.
Sasaki, T., Kato, M., & Takai, Y. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(20)80478-5 · Cited by 73 · see citing works
Norton, A. W., Hosier, S., Terew, J. M., Li, N., Dhingra, A., Vardi, N., Baehr, W., & Cote, R. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m410475200 · Cited by 68 · see citing works
Multiple Cellular Proteins Modulate the Dynamics of K-ras Association with the Plasma Membrane
Bhagatji, P., Leventis, R., Rich, R. L., Lin, C., & Silvius, J. R. (2010) · Biophysical Journal · doi:10.1016/j.bpj.2010.10.001 · Cited by 51 · see citing works
Precise measurement of protein interacting fractions with fluorescence lifetime imaging microscopy
Walther, K. A., Papke, B., Sinn, M. B., Michel, K., & Kinkhabwala, A. (2011) · Molecular BioSystems · doi:10.1039/c0mb00132e · Cited by 45 · see citing works
Spatial cycles in G‐protein crowd control
Vartak, N., & Bastiaens, P. I. H. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.184 · Cited by 38 · see citing works
Self-citationZhang, T., Li, S., Zhang, Y., Zhong, C., Lai, Z., & Ding, J. (2009) · Structure · doi:10.1016/j.str.2009.01.014 · Cited by 37 · see citing works
Phosphodiesterase 6 subunits are expressed and altered in idiopathic pulmonary fibrosis
Nikolova, S., Günther, A., Savai, R., Weißmann, N., Ghofrani, H. A., Königshoff, M., Eickelberg, O., Klepetko, W., Voswinckel, R., Seeger, W., et al. (2010) · Respiratory Research · doi:10.1186/1465-9921-11-146 · Cited by 26 · see citing works
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Cherfils, J., & Zeghouf, M. (2013) · Physiological Reviews · doi:10.1152/physrev.00003.2012 · Cited by 1,245 · see citing works
Small molecule inhibition of the KRAS–PDEδ interaction impairs oncogenic KRAS signalling
Zimmermann, G., Papke, B., Ismail, S., Vartak, N., Chandra, A., Hoffmann, M., Hahn, S. A., Triola, G., Wittinghofer, A., Bastiaens, P. I. H., et al. (2013) · Nature · doi:10.1038/nature12205 · Cited by 596 · see citing works
Self-citationRegulating the regulator: post-translational modification of RAS
Ahearn, I. M., Haigis, K. M., Bar‐Sagi, D., & Philips, M. R. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3255 · Cited by 557 · see citing works
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Wang, M., & Casey, P. J. (2016) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2015.11 · Cited by 540 · see citing works
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Xie, X., Yu, T., Li, X., Zhang, N., Foster, L. J., Peng, C., Huang, W., & He, G. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01589-z · Cited by 396 · see citing works
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Cox, A. D., Der, C. J., & Philips, M. R. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-3214 · Cited by 351 · see citing works
Chandra, A., Grecco, H. E., Pisupati, V., Perera, D., Cassidy, L., Skoulidis, F., Ismail, S. A., Hedberg, C., Hanzal-Bayer, M., Venkitaraman, A. R., et al. (2012) · Nature Cell Biology · doi:10.1038/ncb2394 · Cited by 325 · see citing works
Self-citationAutopalmitoylation of TEAD proteins regulates transcriptional output of the Hippo pathway
Chan, P., Han, X., Zheng, B., DeRan, M., Yu, J., Jarugumilli, G. K., Deng, H., Pan, D., Luo, X., & Wu, X. (2016) · Nature Chemical Biology · doi:10.1038/nchembio.2036 · Cited by 313 · see citing works
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Schmick, M., Vartak, N., Papke, B., Kovacevic, M., Truxius, D. C., Rossmannek, L., & Bastiaens, P. I. H. (2014) · Cell · doi:10.1016/j.cell.2014.02.051 · Cited by 243 · see citing works
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Self-citationJiang, C., Huang, H., Kang, X., Yang, L., Xi, Z., Sun, H., Pluth, M. D., & Yi, L. (2021) · Chemical Society Reviews · doi:10.1039/d0cs01096k · Cited by 213 · see citing works
Protein sorting, targeting and trafficking in photoreceptor cells
Pearring, J. N., Salinas, R. Y., Baker, S. A., & Arshavsky, V. Y. (2013) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2013.03.002 · Cited by 207 · see citing works
Modeling and Rescue of RP2 Retinitis Pigmentosa Using iPSC-Derived Retinal Organoids
Lane, A., Jovanovic, K., Shortall, C., Ottaviani, D., Brugulat-Panés, A., Schwarz, N., Guarascio, R., Hayes, M. J., Palfi, A., Chadderton, N., et al. (2020) · Stem Cell Reports · doi:10.1016/j.stemcr.2020.05.007 · Cited by 184 · see citing works
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Gotthardt, K., Lokaj, M., Koerner, C., Falk, N., Gießl, A., & Wittinghofer, A. (2015) · eLife · doi:10.7554/elife.11859 · Cited by 140 · see citing works
Self-citationThomas, S., Wright, K. J., Corre, S. L., Micalizzi, A., Romani, M., Abhyankar, A., Saada, J., Perrault, I., Amiel, J., Litzler, J., et al. (2013) · Human Mutation · doi:10.1002/humu.22470 · Cited by 123 · see citing works
Structural basis for Arl3‐specific release of myristoylated ciliary cargo from UNC119
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Nozaki, S., Katoh, Y., Terada, M., Michisaka, S., Funabashi, T., Takahashi, S., Kontani, K., & Nakayama, K. (2016) · Journal of Cell Science · doi:10.1242/jcs.197004 · Cited by 92 · see citing works
Martín‐Gago, P., Fansa, E. K., Klein, C. H., Murarka, S., Janning, P., Schürmann, M., Metz, M., Ismail, S., Schultz‐Fademrecht, C., Baumann, M., et al. (2017) · Angewandte Chemie International Edition · doi:10.1002/anie.201610957 · Cited by 89 · see citing works
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Jensen, V. L., & Leroux, M. R. (2017) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2017.03.012 · Cited by 84 · see citing works
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Yang, A., Pantoom, S., & Wu, Y. (2017) · eLife · doi:10.7554/elife.23905 · Cited by 85 · see citing works
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Self-citationDavidson, A. E., Schwarz, N., Zelinger, L., Stern-Schneider, G., Shoemark, A., Spitzbarth, B., Gross, M., Laxer, U., Sosna, J., Sergouniotis, P. I., et al. (2013) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2013.06.003 · Cited by 73 · see citing works
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Schwarz, N., Lane, A., Jovanovic, K., Parfitt, D. A., Aguilà, M., Thompson, C. L., da Cruz, L., Coffey, P. J., Chapple, J. P., Hardcastle, A. J., et al. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx143 · Cited by 71 · see citing works
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Mysore, V. P., Zhou, Z.-W., Ambrogio, C., Li, L., Kapp, J. N., Lu, C., Wang, Q., Tucker, M. R., Okoro, J. J., Nagy‐Davidescu, G., et al. (2021) · Nature Structural & Molecular Biology · doi:10.1038/s41594-021-00667-6 · Cited by 69 · see citing works
Weak membrane interactions allow Rheb to activate mTORC1 signaling without major lysosome enrichment
Angarola, B., & Ferguson, S. (2019) · bioRxiv · doi:10.1091/mbc.e19-03-0146 · Cited by 58 · see citing works
Mazhab‐Jafari, M. T., Marshall, C. B., Stathopulos, P. B., Kobashigawa, Y., Stambolic, V., Kay, L. E., Inagaki, F., & Ikura, M. (2013) · Journal of the American Chemical Society · doi:10.1021/ja312508w · Cited by 69 · see citing works
Post-translational modification of RAS proteins
Campbell, S. L., & Philips, M. R. (2021) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2021.06.015 · Cited by 66 · see citing works
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Cheng, J., Li, Y., Wang, X., Dong, G., & Sheng, C. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00929 · Cited by 67 · see citing works
The interplay between RPGR, PDEδ and Arl2/3 regulate the ciliary targeting of farnesylated cargo
Wätzlich, D., Vetter, I. R., Gotthardt, K., Miertzschke, M., Chen, Y., Wittinghofer, A., & Ismail, S. (2013) · EMBO Reports · doi:10.1038/embor.2013.37 · Cited by 66 · see citing works
Self-citationStructural Biology of Arf and Rab GTPases’ Effector Recruitment and Specificity
Khan, A. R., & Ménétrey, J. (2013) · Structure · doi:10.1016/j.str.2013.06.016 · Cited by 66 · see citing works
Uncoordinated (UNC)119: Coordinating the trafficking of myristoylated proteins
Constantine, R., Zhang, H., Gerstner, C. D., Frederick, J. M., & Baehr, W. (2012) · Vision Research · doi:10.1016/j.visres.2012.08.012 · Cited by 65 · see citing works
Mistrafficking of prenylated proteins causes retinitis pigmentosa 2
Zhang, H., Hanke‐Gogokhia, C., Jiang, L., Li, X., Wang, P., Gerstner, C. D., Frederick, J. M., Yang, Z., & Baehr, W. (2014) · The FASEB Journal · doi:10.1096/fj.14-257915 · Cited by 64 · see citing works
Structure of the RZZ complex and molecular basis of its interaction with Spindly
Mosalaganti, S., Keller, J., Altenfeld, A., Winzker, M., Rombaut, P., Saur, M., Petrović, A., Wehenkel, A. M., Wohlgemuth, S., Müller, F., et al. (2017) · The Journal of Cell Biology · doi:10.1083/jcb.201611060 · Cited by 63 · see citing works
Self-citationZimmermann, G., Schultz‐Fademrecht, C., Küchler, P., Murarka, S., Ismail, S., Triola, G., Nußbaumer, P., Wittinghofer, A., & Waldmann, H. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm500632s · Cited by 63 · see citing works
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Tnimov, Z., Guo, Z., Gambin, Y., Nguyen, U. T. T., Wu, Y., Abankwa, D., Stigter, A., Collins, B. M., Waldmann, H., Goody, R. S., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.371294 · Cited by 63 · see citing works
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Baehr, W., Hanke‐Gogokhia, C., Sharif, A. S., Reed, M., Dahl, T. M., Frederick, J. M., & Ying, G. (2018) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2018.12.004 · Cited by 60 · see citing works
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Xue, G., Xie, J., Hinterndorfer, M., Cigler, M., Dötsch, L., Imrichová, H., Lampe, P., Cheng, X., Adariani, S. R., Winter, G. E., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-43657-6 · Cited by 61 · see citing works
Self-citationVPS35 binds farnesylated N-Ras in the cytosol to regulate N-Ras trafficking
Zhou, M., Wiener, H. H., Su, W., Zhou, Y., Liot, C., Ahearn, I. M., Hancock, J. F., & Philips, M. R. (2016) · The Journal of Cell Biology · doi:10.1083/jcb.201604061 · Cited by 56 · see citing works
Chemical Synthesis and Semisynthesis of Lipidated Proteins
Hanna, C. C., Kriegesmann, J., Dowman, L. J., Becker, C. F. W., & Payne, R. J. (2021) · Angewandte Chemie International Edition · doi:10.1002/anie.202111266 · Cited by 55 · see citing works
Arl3 and RP2 mediated assembly and traffic of membrane associated cilia proteins
Schwarz, N., Hardcastle, A. J., & Cheetham, M. E. (2012) · Vision Research · doi:10.1016/j.visres.2012.07.016 · Cited by 54 · see citing works
Leung, E. L., Luo, L. X., Liu, Z. Q., Wong, V. K. W., Lu, L., Xie, Y., Zhang, N., Qu, Y. Q., Fan, X., Li, Y., et al. (2018) · Cell Death and Disease · doi:10.1038/s41419-017-0065-9 · Cited by 54 · see citing works
Membrane Protein Transport in Photoreceptors: The Function of PDE
Baehr, W. (2014) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.14-16066 · Cited by 53 · see citing works
G protein gamma subunit, a hidden master regulator of GPCR signaling
Kankanamge, D., Tennakoon, M., Karunarathne, A., & Gautam, N. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102618 · Cited by 52 · see citing works
Emmanouilidis, L., Schütz, U., Tripsianes, K., Madl, T., Radke, J., Rucktäschel, R., Wilmanns, M., Schliebs, W., Erdmann, R., & Sattler, M. (2017) · Nature Communications · doi:10.1038/ncomms14635 · Cited by 50 · see citing works
A semisynthetic Atg3 reveals that acetylation promotes Atg3 membrane binding and Atg8 lipidation
Li, Y.-T., Yi, C., Chen, C., Lan, H., Pan, M., Zhang, S.-J., Huang, Y., Guan, C.-J., Li, Y., Yu, L., et al. (2017) · Nature Communications · doi:10.1038/ncomms14846 · Cited by 52 · see citing works
ARL3 regulates trafficking of prenylated phototransduction proteins to the rod outer segment
Wright, Z. C., Singh, R. K., Alpino, R., Goldberg, A. F. X., Sokolov, M., & Ramamurthy, V. (2016) · Human Molecular Genetics · doi:10.1093/hmg/ddw077 · Cited by 51 · see citing works
The prenyl-binding protein PrBP/δ: A chaperone participating in intracellular trafficking
Zhang, H., Constantine, R., Frederick, J. M., & Baehr, W. (2012) · Vision Research · doi:10.1016/j.visres.2012.08.013 · Cited by 51 · see citing works
Zverina, E. A., Lamphear, C. L., Wright, E. N., & Fierke, C. A. (2012) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2012.10.015 · Cited by 51 · see citing works
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Newman, L. E., Zhou, C., Mudigonda, S., Mattheyses, A. L., Paradies, E., Marobbio, C. M. T., & Kahn, R. (2014) · PLoS ONE · doi:10.1371/journal.pone.0099270 · Cited by 50 · see citing works
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Triola, G., Waldmann, H., & Hedberg, C. (2011) · ACS Chemical Biology · doi:10.1021/cb200460u · Cited by 50 · see citing works
Self-citationDrug for an 'undruggable' protein
Baker, N. M., & Der, C. J. (2013) · Nature · doi:10.1038/nature12248 · Cited by 49 · see citing works
Sorting of lipidated cargo by the Arl2/Arl3 system
Fansa, E. K., & Wittinghofer, A. (2016) · Small GTPases · doi:10.1080/21541248.2016.1224454 · Cited by 49 · see citing works
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Ray, A., Jatana, N., & Thukral, L. (2017) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2017.01.002 · Cited by 49 · see citing works
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Lyraki, R., Lokaj, M., Soares, D. C., Little, A., Vermeren, M., Marsh, J. A., Wittinghofer, A., & Hurd, T. W. (2018) · Journal of Cell Science · doi:10.1242/jcs.211748 · Cited by 47 · see citing works
Self-citationARL3 is downregulated and acts as a prognostic biomarker in glioma
Wang, Y., Zhao, W., Liu, X., Guan, G., & Zhuang, M. (2019) · Journal of Translational Medicine · doi:10.1186/s12967-019-1914-3 · Cited by 47 · see citing works
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Sperlich, B., Kapoor, S., Waldmann, H., Winter, R., & Weise, K. (2016) · Biophysical Journal · doi:10.1016/j.bpj.2016.05.042 · Cited by 47 · see citing works
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Siddiqui, F. A., Alam, C., Rosenqvist, P., Ora, M., Sabt, A., Manoharan, G. B., Bindu, L., Okutachi, S., Catillon, M., Taylor, T., et al. (2020) · ACS Omega · doi:10.1021/acsomega.9b03639 · Cited by 46 · see citing works
Jaiswal, M., Fansa, E. K., Kösling, S. K., Mejuch, T., Waldmann, H., & Wittinghofer, A. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.741827 · Cited by 47 · see citing works
Self-citationZhou, Y., Prakash, P., Hong, L., Gorfe, A. A., & Hancock, J. F. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2014605118 · Cited by 46 · see citing works
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Winzker, M., Friese, A., Koch, U., Janning, P., Ziegler, S., & Waldmann, H. (2019) · Angewandte Chemie International Edition · doi:10.1002/anie.201913904 · Cited by 45 · see citing works
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Zhang, Q., Hu, J., & Ling, K. (2013) · Experimental Cell Research · doi:10.1016/j.yexcr.2013.03.024 · Cited by 44 · see citing works
Leung, E. L., Luo, L. X., Li, Y., Liu, Z., Li, L. L., Shi, D. F., Xie, Y., Huang, M., Lu, L. L., Duan, F. G., et al. (2019) · International Journal of Cancer · doi:10.1002/ijc.32222 · Cited by 39 · see citing works
Caviglia, S., Brankatschk, M., Fischer, E. J., Eaton, S., & Luschnig, S. (2016) · Nature Cell Biology · doi:10.1038/ncb3374 · Cited by 40 · see citing works
Coordination of Rheb lysosomal membrane interactions with mTORC1 activation
Angarola, B. L., & Ferguson, S. M. (2020) · F1000Research · doi:10.12688/f1000research.22367.1 · Cited by 39 · see citing works
ARF family GTPases with links to cilia
Fisher, S. I., Kuna, D., Caspary, T., Kahn, R., & Sztul, E. S. (2020) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00188.2020 · Cited by 38 · see citing works
Sot, B., Behrmann, E., Raunser, S., & Wittinghofer, A. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1201658110 · Cited by 40 · see citing works
Self-citationO’Neill, P., Karunarathne, A., Kalyanaraman, V., Silvius, J. R., & Gautam, N. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1205345109 · Cited by 39 · see citing works
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Majumder, A., Gopalakrishna, K. N., Cheguru, P., Gakhar, L., & Artemyev, N. O. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.476242 · Cited by 38 · see citing works
Phosphorylation Weakens but Does Not Inhibit Membrane Binding and Clustering of K-Ras4B
Zhang, S.-Y., Sperlich, B., Li, F.-Y., Al-Ayoubi, S. R., Chen, H.-X., Zhao, Y., Li, Y., Weise, K., Winter, R., & Chen, Y. (2017) · ACS Chemical Biology · doi:10.1021/acschembio.7b00165 · Cited by 38 · see citing works
Self-citationDisease mechanisms of X-linked retinitis pigmentosa due to RP2 and RPGR mutations
Lyraki, R., Megaw, R. D., & Hurd, T. W. (2016) · Biochemical Society Transactions · doi:10.1042/bst20160148 · Cited by 37 · see citing works
ARL2 overexpression inhibits glioma proliferation and tumorigenicity via down-regulating AXL
Wang, Y., Guan, G., Cheng, W., Jiang, Y., Shan, F., Wu, A., Cheng, P., & Guo, Z. (2018) · BMC Cancer · doi:10.1186/s12885-018-4517-0 · Cited by 36 · see citing works
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Gorfe, A. A., & Cho, K. (2019) · Small GTPases · doi:10.1080/21541248.2019.1655883 · Cited by 36 · see citing works
The X-linked retinitis pigmentosa protein RP2 facilitates G protein traffic
Schwarz, N., Novoselova, T. V., Wait, R., Hardcastle, A. J., & Cheetham, M. E. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr520 · Cited by 35 · see citing works
Spatial regulation of mTORC1 signalling: Beyond the Rag GTPases
Carroll, B. (2020) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2020.02.007 · Cited by 34 · see citing works
Development of Pyridazinone Chemotypes Targeting the PDEδ Prenyl Binding Site
Murarka, S., Martín‐Gago, P., Schultz‐Fademrecht, C., Saabi, A. A., Baumann, M., Fansa, E. K., Ismail, S., Nußbaumer, P., Wittinghofer, A., & Waldmann, H. (2016) · Chemistry - A European Journal · doi:10.1002/chem.201603222 · Cited by 34 · see citing works
Self-citationWeise, K., Kapoor, S., Werkmüller, A., Möbitz, S., Zimmermann, G., Triola, G., Waldmann, H., & Winter, R. (2012) · Journal of the American Chemical Society · doi:10.1021/ja305518h · Cited by 34 · see citing works
Self-citationDiscovery of Novel KRAS-PDEδ Inhibitors by Fragment-Based Drug Design
Chen, L., Zhuang, C., Lu, J., Jiang, Y., & Sheng, C. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00057 · Cited by 33 · see citing works
Sharif, A. S., Gerstner, C. D., Cady, M. A., Arshavsky, V. Y., Mitchell, C. A., Ying, G., Frederick, J. M., & Baehr, W. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100529 · Cited by 33 · see citing works
Structural Biology-Inspired Discovery of Novel KRAS–PDEδ Inhibitors
Jiang, Y., Zhuang, C., Chen, L., Lu, J., Dong, G., Miao, Z., Zhang, W., Li, J., & Sheng, C. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b01243 · Cited by 34 · see citing works
- Authors
- Ismail, S. A., Chen, Y.-X., Rusinova, A., Chandra, A., Bierbaum, M., Gremer, L., Triola, G., Waldmann, H., Bastiaens, P. I. H., & Wittinghofer, A.
- Affiliations
- Max Planck Institute of Molecular Physiology (DE)
- Max Planck Society (DE)
- TU Dortmund University (DE)
- Corresponding author
- Wittinghofer, Alfred
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2011-10-16
- Volume
- 7
- Issue
- 12
- Pages
- 942-949
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- OpenAlex
- W1979111896
- Cited by
- 252
- References
- 47
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 5 · 2023: 11 · 2022: 12 · 2021: 22 · 2020: 16 · 2019: 21 · 2018: 23 · 2017: 24 · 2016: 27 · 2015: 11 · 2014: 20 · 2013: 19 · 2012: 17
- FWCI
- 7.91
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- DORA PSI (Paul Scherrer Institute) (submittedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- ARL2, ARL3, guanine nucleotide dissociation inhibitor, Rheb, PDEδ, Rab GTPases, Rho GTPases, protein complex structure, anticancer drug targets
- MeSH terms
- Animals, Biological Transport, Cells, Cultured, Dogs, Guanosine Triphosphate, Humans, Models, Molecular, Protein Conformation, GTP-Binding Proteins, ADP-Ribosylation Factors, Cyclic Nucleotide Phosphodiesterases, Type 6, Prenylation
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