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Manipulating signaling at will: chemically-inducible dimerization (CID) techniques resolve problems in cell biology

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Abstract

Chemically-inducible dimerization (CID) is a powerful tool that has proved useful in solving numerous problems in cell biology and related fields. In this review, we focus on case studies where CID was able to provide insight into otherwise refractory problems. Of particular interest are the cases of lipid second messengers and small GTPases, where the “signaling paradox” (how a small pool of signaling molecules can generate a large range of responses) can be at least partly explained through results gleaned from CID experiments. We also discuss several recent technical advances that provide improved specificity in CID action, novel CID substrates that allow simultaneous orthogonal manipulation of multiple systems in one cell, and several applications that move beyond the traditional CID technique of moving a protein of interest to a specific spatiotemporal location.

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References

  1. Abe N, Inoue T, Galvez T, Klein L, Meyer T (2008) Dissecting the role of PtdIns(4,5)P2 in endocytosis and recycling of the transferring receptor. J Cell Sci 121:1488–1494

    Article  PubMed  CAS  Google Scholar 

  2. Bingol B, Wang CF, Arnott D, Cheng D, Peng J, Sheng M (2010) Autophosphorylated CaMKIIα acts as a scaffold to recruit proteasomes to dendritic spines. Cell 140:567–578

    Article  PubMed  CAS  Google Scholar 

  3. Castellano F, Montcourrier P, Chavrier P (2000) Membrane recruitment of Rac1 triggers phagocytosis. J Cell Sci 113:2955–2961

    PubMed  CAS  Google Scholar 

  4. Csordas G, Varnai P, Golenar T, Roy S, Purkins G, Schneider TG, Balla T, Hajnoczky G (2010) Imaging interorganelle contacts and local calcium dynamics at the ER-mitochondrial interface. Mol Cell 39:121–132

    Article  PubMed  CAS  Google Scholar 

  5. Fegan A, White B, Carlson JCT, Wagner CR (2010) Chemically controlled protein assembly: techniques and applications. Chem Rev 110:3315–3336

    Article  PubMed  CAS  Google Scholar 

  6. Fili N, Calleja V, Woscholski R, Parker PJ, Larjani B (2006) Compartmental signal modulation: endosomal phosphatidylinositol 3-phosphate controls endosome morphology and selective cargo sorting. Proc Nat Acad Sci USA 103:15473–15478

    Article  PubMed  CAS  Google Scholar 

  7. Fivaz M, Bandara S, Inoue T, Meyer T (2008) Robust neuronal symmetry breaking by Ras-triggered local positive feedback. Curr Biol 18:44–50

    Article  PubMed  CAS  Google Scholar 

  8. Graef IA, Holsinger LJ, Diver S, Schreiber SL, Crabtree GR (1997) Proximity and orientation underlie signaling by the non-receptor tyrosine kinase ZAP70. EMBO J 16:5618–5628

    Article  PubMed  CAS  Google Scholar 

  9. Haruki H, Nishikawa J, Laemmli UK (2008) The anchor-away technique: rapid, conditional establishment of yeast mutant phenotypes. Mol Cell 31:925–932

    Article  PubMed  CAS  Google Scholar 

  10. Inoue T, Meyer T (2008) Synthetic activation of endogenous PI3K and Rac identifies an AND-gate switch for cell polarization and migration. PLoS One 3(8):e3068

    Article  PubMed  Google Scholar 

  11. Karginov AV, Ding F, Kota P, Dokholyan NV, Hahn KM (2010) Engineered allosteric activation of kinases in living cells. Nat Biotechnol 28:743–747

    Article  PubMed  CAS  Google Scholar 

  12. Karginov AV, Zou Y, Shirvanyants D, Kota P, Dokholyan NV, Young DD, Hahn KM, Deiters A (2011) Light regulation of protein dimerization and kinase activity in living cells using photocaged rapamycin and engineered FKBP. J Am Chem Soc 133:420–423

    Article  PubMed  CAS  Google Scholar 

  13. Komatsu T, Kukelyansky I, McCaffrey JM, Ueno T, Varela LC, Inoue T (2010) Nat Method 7:206–208

    Article  CAS  Google Scholar 

  14. Li B, Desai SA, MacCokle-Chosnek RA, Fan L, Spencer DM (2002) A novel conditional Akt “survival switch” reversibly protects cells from apoptosis. Gene Ther 9:233–244

    Article  PubMed  CAS  Google Scholar 

  15. Liang FS, Ho WQ, Crabtree GR (2011) Engineering the ABA plant stress pathway for regulation of induced proximity. Sci Signal 4(164):rs2

    Article  PubMed  Google Scholar 

  16. Luik RM, Wang B, Prakriya M, Wu MM, Lewis RS (2008) Oligomerization of STIM1 couples ER calcium depletion to CRAC channel activation. Nature 454:538–542

    Article  PubMed  CAS  Google Scholar 

  17. Marshall CJ (1995) Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80:179–185

    Article  PubMed  CAS  Google Scholar 

  18. Miyamoto T, DeRose R, Suarez A, Ueno T, Chen M, Sun T, Wolfgang MJ, Mukherjee C, Meyers DJ, Inoue T (2012) Rapid and orthogonal logic gating with a gibberellin-induced dimerization system. Nat Chem Biol 8:465–470

    Article  PubMed  CAS  Google Scholar 

  19. Mor A, Philips MR (2006) Compartmentalized Ras/MAPK signaling. Annu Rev Immunol 24:771–800

    Article  PubMed  CAS  Google Scholar 

  20. Phua SC, Pohlmeyer C, Inoue T (2012) Rapidly relocating molecules between organelles to manipulate small GTPase activity. ACS Chem Biol. doi:10.1021/cb300280k

  21. Putyrski M, Schultz C (2012) Protein translocation as a tool: the current rapamycin story. FEBS Lett. doi:10.1016/j.febslet.2012.04.061

  22. Rahdar M, Inoue T, Meyer T, Zhang J, Vazquez F, Devreotes PN (2009) A phosphorylation-dependent intramolecular interaction regulates the membrane association and activity of the tumor suppressor PTEN. Proc Nat Acad Sci USA 106:480–485

    Article  PubMed  CAS  Google Scholar 

  23. Robinson MS, Sahlender DA, Foster SD (2010) Rapid inactivation of proteins by rapamycin-induced rerouting to mitochondria. Dev Cell 18:324–331

    Article  PubMed  CAS  Google Scholar 

  24. Suh BC, Inoue T, Meyer T, Hille B (2006) Rapid chemically induced changes of PtdIns(4,5)P2 gate KCNQ ion channels. Science 314:1454–1457

    Article  PubMed  CAS  Google Scholar 

  25. Terrillon S, Bouvier M (2004) Receptor activity-independent recruitment of βarrestin2 reveals specific signaling modes. EMBO J 23:3950–3961

    Article  PubMed  CAS  Google Scholar 

  26. Ueno T, Falkenburger BH, Pohlmeyer C, Inoue T (2011) Triggering actin comets versus membrane ruffles: distinctive effects of phosphoinositides on actin reorganization. Sci Signal 4(203):ra87

    Article  PubMed  CAS  Google Scholar 

  27. Umeda N, Ueno T, Pohlmeyer C, Nagano T, Inoue T (2011) A photocleavable rapamycin conjugate for spatiotemporal control of small GTPase activity. J Am Chem Soc 133:12–14

    Article  PubMed  CAS  Google Scholar 

  28. Varnai P, Thyagarajan B, Rohacs T, Balla T (2006) Rapidly inducible changes in phosphatidylinositol 4,5-bisphosphate levels influence multiple regulatory functions of the lipid in intact living cells. J Cell Biol 175:377–382

    Article  PubMed  CAS  Google Scholar 

  29. Varnai P, Toth B, Toth DJ, Hunyady L, Balla T (2007) Visualization and manipulation of plasma membrane-endoplasmic reticulum contact sites indicates the presence of additional molecular components within the STIM1-Orai1 complex. J Biol Chem 282:29678–29690

    Article  PubMed  CAS  Google Scholar 

  30. Zoncu R, Perera RM, Sebastian R, Nakatsu F, Chen H, Balla T, Ayala G, Toomre D, De Camilli PV (2007) Loss of endocytic clathrin-coated pits upon acute depletion of phosphatidylinositol 4,5-bisphosphate. Proc Nat Acad Sci USA 104:3793–3798

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors’ research was supported by NIH grants GM092930 to T.I. We regret that due to length considerations, we could not discuss many worthwhile papers that have appeared in the literature over the years.

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Correspondence to Takanari Inoue.

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This article is a submission for the special issue on “Recent Advances in Tools for Measuring and Manipulating Biochemical Signals and Mechanical Forces in Living Cells.”

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DeRose, R., Miyamoto, T. & Inoue, T. Manipulating signaling at will: chemically-inducible dimerization (CID) techniques resolve problems in cell biology. Pflugers Arch - Eur J Physiol 465, 409–417 (2013). https://doi.org/10.1007/s00424-012-1208-6

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  • DOI: https://doi.org/10.1007/s00424-012-1208-6

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