Regulatory Roles of HSP90-Rich Extracellular Vesicles

  • Takanori EguchiEmail author
  • Kisho Ono
  • Kazumi Kawata
  • Kuniaki Okamoto
  • Stuart K. Calderwood
Part of the Heat Shock Proteins book series (HESP, volume 19)


HSP90 is an essential protein in protein folding, cancer progression and wound healing. Originally, most studies were focused on the intracellular molecular chaperone role of HSP90. However, more recent studies, including ours, have reported the secretion of HSP90 and novel functions for this protein in the extracellular space (ex-HSP90). Additionally, HSP90 has been found to be a major cargo contained in extracellular vesicles (EV) such as exosomes. HSP90 can directly bind to and promote functions of CD91/LRP1 and receptor tyrosine kinases such as EGF receptor. HSP90 also regulates the recycling of Rab proteins that control the secretion of exosomes. This chapter reviews current knowledge and the future potential of ex-HSP90 and EV-HSP90.


Ectosome Epithelial-mesenchymal transition Exosome Extracellular matrix Extracellular vesicle HSP90 LRP1/CD91 Rab proteins 



Extracellular matrix


Epidermal growth factor receptor


Epithelial-mesenchymal transition


Extracellular vesicle


Extracellular HSP90




Hypoxia-inducible factor-1


Head and neck cancer


Heat shock protein


Intracellular HSP90


Lipoprotein receptor-related protein 1




Multivesicular body


Oral squamous cell carcinoma


Receptor tyrosine kinase




Thrombospondin 1



This paper is dedicated to the memory of one of our mentors, Professor Ken-ichi Kozaki, who passed away on May 29, 2016. The authors thank Yuka Okusha, Chiharu Sogawa, Masaharu Takigawa, Sati Kubota, Akira Sasaki, Ayesha Murshid, Thomas Prince, and Benjamin Lang for useful discussion and helpful suggestion. This work was supported by JSPS KAKENHI, grant numbers JP17K11642 (TE), JP17K11643 (TE), JP17K11669 (TE), JP16K11863 (KOk), JP18K09789 (TE) and by SUZUKEN memorial foundation (TE).


  1. Actis Dato V, Chiabrando GA (2018) The role of low-density lipoprotein receptor-related protein 1 in lipid metabolism, glucose homeostasis and inflammation. Int J Mol Sci 19(6)Google Scholar
  2. Barile L, Vassalli G (2017) Exosomes: therapy delivery tools and biomarkers of diseases. Pharmacol Ther 174:63–78CrossRefGoogle Scholar
  3. Beveridge TJ (1999) Structures of gram-negative cell walls and their derived membrane vesicles. J Bacteriol 181:4725–4733PubMedPubMedCentralGoogle Scholar
  4. Boel NM, Hunter MC, Edkins AL (2018) LRP1 is required for novobiocin-mediated fibronectin turnover. Sci Rep 8:11438CrossRefPubMedPubMedCentralGoogle Scholar
  5. Burgess JW, Stanley KK (1997) Estrogen-stimulated transcytosis of desialylated ligands and alpha2 macroglobulin in rat liver. Biochim Biophys Acta 1359:48–58CrossRefGoogle Scholar
  6. Carstens JL, Correa de Sampaio P, Yang D, Barua S, Wang H, Rao A, Allison JP, LeBleu VS, Kalluri R (2017) Spatial computation of intratumoral T cells correlates with survival of patients with pancreatic cancer. Nat Commun 8:15095CrossRefPubMedPubMedCentralGoogle Scholar
  7. Chavrier P, Goud B (1999) The role of ARF and Rab GTPases in membrane transport. Curr Opin Cell Biol 11:466–475CrossRefGoogle Scholar
  8. Chen CY, Balch WE (2006) The Hsp90 chaperone complex regulates GDI-dependent Rab recycling. Mol Biol Cell 17:3494–3507CrossRefPubMedPubMedCentralGoogle Scholar
  9. Cheng CF, Fan J, Fedesco M, Guan S, Li Y, Bandyopadhyay B, Bright AM, Yerushalmi D, Liang M, Chen M, Han YP, Woodley DT, Li W (2008) Transforming growth factor alpha (TGFalpha)-stimulated secretion of HSP90alpha: using the receptor LRP-1/CD91 to promote human skin cell migration against a TGFbeta-rich environment during wound healing. Mol Cell Biol 28:3344–3358PubMedPubMedCentralGoogle Scholar
  10. Cheng CF, Sahu D, Tsen F, Zhao Z, Fan J, Kim R, Wang X, O’Brien K, Li Y, Kuang Y, Chen M, Woodley DT, Li W (2011) A fragment of secreted Hsp90alpha carries properties that enable it to accelerate effectively both acute and diabetic wound healing in mice. J Clin Invest 121:4348–4361PubMedPubMedCentralGoogle Scholar
  11. Dhanani KCH, Samson WJ, Edkins AL (2017) Fibronectin is a stress responsive gene regulated by HSF1 in response to geldanamycin. Sci Rep 7:17617CrossRefPubMedPubMedCentralGoogle Scholar
  12. Dong H, Zou M, Bhatia A, Jayaprakash P, Hofman F, Ying Q, Chen M, Woodley DT, Li W (2016) Breast Cancer MDA-MB-231 cells use secreted heat shock protein-90alpha (Hsp90alpha) to survive a hostile hypoxic environment. Sci Rep 6:20605CrossRefPubMedPubMedCentralGoogle Scholar
  13. Eguchi T, Sogawa C, Okusha Y, Uchibe K, Iinuma R, Ono K, Nakano K, Murakami J, Itoh M, Arai K, Fujiwara T, Namba Y, Murata Y, Shimomura M, Okamura H, Takigawa M, Nakatsura T, Kozaki K, Okamoto K, Calderwood S (2018) Organoids with cancer stem cell-like properties secrete exosomes and HSP90 in a 3D nanoenvironment. PLoS One 13:e0191109CrossRefPubMedPubMedCentralGoogle Scholar
  14. Eustace BK, Sakurai T, Stewart JK, Yimlamai D, Unger C, Zehetmeier C, Lain B, Torella C, Henning SW, Beste G, Scroggins BT, Neckers L, Ilag LL, Jay DG (2004) Functional proteomic screens reveal an essential extracellular role for hsp90 alpha in cancer cell invasiveness. Nat Cell Biol 6:507–514Google Scholar
  15. Fais S, O’Driscoll L, Borras FE, Buzas E, Camussi G, Cappello F, Carvalho J, Cordeiro da Silva A, Del Portillo H, El Andaloussi S, Ficko Trcek T, Furlan R, Hendrix A, Gursel I, Kralj-Iglic V, Kaeffer B, Kosanovic M, Lekka ME, Lipps G, Logozzi M, Marcilla A, Sammar M, Llorente A, Nazarenko I, Oliveira C, Pocsfalvi G, Rajendran L, Raposo G, Rohde E, Siljander P, van Niel G, Vasconcelos MH, Yanez-Mo M, Yliperttula ML, Zarovni N, Zavec AB, Giebel B (2016) Evidence-based clinical use of nanoscale extracellular vesicles in nanomedicine. ACS Nano 10:3886–3899CrossRefGoogle Scholar
  16. Fillebeen C, Descamps L, Dehouck MP, Fenart L, Benaissa M, Spik G, Cecchelli R, Pierce A (1999) Receptor-mediated transcytosis of lactoferrin through the blood-brain barrier. J Biol Chem 274:7011–7017CrossRefGoogle Scholar
  17. Fujita Y, Yoshioka Y, Ochiya T (2016) Extracellular vesicle transfer of cancer pathogenic components. Cancer Sci 107:385–390CrossRefPubMedPubMedCentralGoogle Scholar
  18. Fujiwara T, Eguchi T, Sogawa C, Ono K, Murakami J, Ibaragi S, Asaumi J, Okamoto K, Calderwood S, Kozaki K (2018a) Anti-EGFR antibody cetuximab is secreted by oral squamous cell carcinoma and alters EGF-driven mesenchymal transition. Biochem Biophys Res Commun 503:1267–1272CrossRefGoogle Scholar
  19. Fujiwara T, Eguchi T, Sogawa C, Ono K, Murakami J, Ibaragi S, Asaumi J-i, Calderwood SK, Okamoto K, Kozaki K-i (2018b) Carcinogenic epithelial-mesenchymal transition initiated by oral cancer exosomes is inhibited by anti-EGFR antibody cetuximab. Oral Oncol 86:251–257CrossRefGoogle Scholar
  20. Ha D, Yang N, Nadithe V (2016) Exosomes as therapeutic drug carriers and delivery vehicles across biological membranes: current perspectives and future challenges. Acta Pharm Sin B 6:287–296CrossRefPubMedPubMedCentralGoogle Scholar
  21. Hance MW, Dole K, Gopal U, Bohonowych JE, Jezierska-Drutel A, Neumann CA, Liu H, Garraway IP, Isaacs JS (2012) Secreted Hsp90 is a novel regulator of the epithelial to mesenchymal transition (EMT) in prostate cancer. J Biol Chem 287:37732–37744CrossRefPubMedPubMedCentralGoogle Scholar
  22. Horibe S, Tanahashi T, Kawauchi S, Murakami Y, Rikitake Y (2018) Mechanism of recipient cell-dependent differences in exosome uptake. BMC Cancer 18:47CrossRefPubMedPubMedCentralGoogle Scholar
  23. Hsu C, Morohashi Y, Yoshimura S, Manrique-Hoyos N, Jung S, Lauterbach MA, Bakhti M, Gronborg M, Mobius W, Rhee J, Barr FA, Simons M (2010) Regulation of exosome secretion by Rab35 and its GTPase-activating proteins TBC1D10A-C. J Cell Biol 189:223–232CrossRefPubMedPubMedCentralGoogle Scholar
  24. Hunter MC, O’Hagan KL, Kenyon A, Dhanani KC, Prinsloo E, Edkins AL (2014) Hsp90 binds directly to fibronectin (FN) and inhibition reduces the extracellular fibronectin matrix in breast cancer cells. PLoS One 9:e86842CrossRefPubMedPubMedCentralGoogle Scholar
  25. Jarosz-Griffiths HH, Noble E, Rushworth JV, Hooper NM (2016) Amyloid-beta receptors: the good, the bad, and the prion protein. J Biol Chem 291:3174–3183CrossRefPubMedPubMedCentralGoogle Scholar
  26. Jayaprakash P, Dong H, Zou M, Bhatia A, O’Brien K, Chen M, Woodley DT, Li W (2015) Hsp90alpha and Hsp90beta together operate a hypoxia and nutrient paucity stress-response mechanism during wound healing. J Cell Sci 128:1475–1480CrossRefPubMedPubMedCentralGoogle Scholar
  27. Kalluri R (2016) The biology and function of exosomes in cancer. J Clin Invest 126:1208–1215CrossRefPubMedPubMedCentralGoogle Scholar
  28. Kalluri R, LeBleu VS (2016) Discovery of double-stranded genomic DNA in circulating exosomes. Cold Spring Harb Symp Quant Biol 81:275–280CrossRefPubMedPubMedCentralGoogle Scholar
  29. Kawata K, Kubota S, Eguchi T, Aoyama E, Moritani NH, Kondo S, Nishida T, Takigawa M (2012) Role of LRP1 in transport of CCN2 protein in chondrocytes. J Cell Sci 125:2965–2972CrossRefPubMedPubMedCentralGoogle Scholar
  30. Koong AC, Denko NC, Hudson KM, Schindler C, Swiersz L, Koch C, Evans S, Ibrahim H, Le QT, Terris DJ, Giaccia AJ (2000) Candidate genes for the hypoxic tumor phenotype. Cancer Res 60:883–887PubMedPubMedCentralGoogle Scholar
  31. Kouranti I, Sachse M, Arouche N, Goud B, Echard A (2006) Rab35 regulates an endocytic recycling pathway essential for the terminal steps of cytokinesis. Curr Biol 16:1719–1725CrossRefGoogle Scholar
  32. LePage GA (1948) Phosphorylated intermediates in tumor glycolysis; effects of anoxia and hyperglycemia. Cancer Res 8:201Google Scholar
  33. Leca J, Martinez S, Lac S, Nigri J, Secq V, Rubis M, Bressy C, Serge A, Lavaut MN, Dusetti N, Loncle C, Roques J, Pietrasz D, Bousquet C, Garcia S, Granjeaud S, Ouaissi M, Bachet JB, Brun C, Iovanna JL, Zimmermann P, Vasseur S, Tomasini R (2016) Cancer-associated fibroblast-derived annexin A6+ extracellular vesicles support pancreatic cancer aggressiveness. J Clin Invest 126:4140–4156CrossRefPubMedPubMedCentralGoogle Scholar
  34. Li W, Li Y, Guan S, Fan J, Cheng CF, Bright AM, Chinn C, Chen M, Woodley DT (2007) Extracellular heat shock protein-90alpha: linking hypoxia to skin cell motility and wound healing. EMBO J 26:1221–1233CrossRefPubMedPubMedCentralGoogle Scholar
  35. Ma L, Li Y, Peng J, Wu D, Zhao X, Cui Y, Chen L, Yan X, Du Y, Yu L (2015) Discovery of the migrasome, an organelle mediating release of cytoplasmic contents during cell migration. Cell Res 25:24–38CrossRefGoogle Scholar
  36. Marynen P, Van der Schueren B, Van Leuven F, Cassiman JJ, Van den Berghe H (1982) Absence of specific binding of receptor-mediated endocytosis, and of secretion of alpha-2-macroglobulin by cultured endothelial cells. Haemostasis 11:210–214PubMedGoogle Scholar
  37. Masuda ES, Luo Y, Young C, Shen M, Rossi AB, Huang BC, Yu S, Bennett MK, Payan DG, Scheller RH (2000) Rab37 is a novel mast cell specific GTPase localized to secretory granules. FEBS Lett 470:61–64CrossRefGoogle Scholar
  38. Mathiyalagan P, Liang Y, Kim D, Misener S, Thorne T, Kamide CE, Klyachko E, Losordo DW, Hajjar RJ, Sahoo S (2017) Angiogenic mechanisms of human CD34+ stem cell exosomes in the repair of ischemic hindlimb. Circ Res 120:1466–1476CrossRefPubMedPubMedCentralGoogle Scholar
  39. Melentijevic I, Toth ML, Arnold ML, Guasp RJ, Harinath G, Nguyen KC, Taub D, Parker JA, Neri C, Gabel CV, Hall DH, Driscoll M (2017) C. elegans neurons jettison protein aggregates and mitochondria under neurotoxic stress. Nature 542:367–371CrossRefPubMedPubMedCentralGoogle Scholar
  40. Mendt M, Kamerkar S, Sugimoto H, McAndrews KM, Wu CC, Gagea M, Yang S, Blanko EVR, Peng Q, Ma X, Marszalek JR, Maitra A, Yee C, Rezvani K, Shpall E, LeBleu VS, Kalluri R (2018) Generation and testing of clinical-grade exosomes for pancreatic cancer. JCI Insight 3:8CrossRefGoogle Scholar
  41. Meng H, Chen G, Zhang X, Wang Z, Thomas DG, Giordano TJ, Beer DG, Wang MM (2011) Stromal LRP1 in lung adenocarcinoma predicts clinical outcome. Clin Cancer Res 17:2426–2433CrossRefPubMedPubMedCentralGoogle Scholar
  42. Meng J, Chen S, Lei YY, Han JX, Zhong WL, Wang XR, Liu YR, Gao WF, Zhang Q, Tan Q, Liu HJ, Zhou HG, Sun T, Yang C (2019) Hsp90beta promotes aggressive vasculogenic mimicry via epithelial-mesenchymal transition in hepatocellular carcinoma. Oncogene 38:228–243CrossRefGoogle Scholar
  43. Minciacchi VR, Spinelli C, Reis-Sobreiro M, Cavallini L, You S, Zandian M, Li X, Mishra R, Chiarugi P, Adam RM, Posadas EM, Viglietto G, Freeman MR, Cocucci E, Bhowmick NA, Di Vizio D (2017a) MYC mediates large oncosome-induced fibroblast reprogramming in prostate cancer. Cancer Res 77:2306–2317CrossRefGoogle Scholar
  44. Minciacchi VR, Zijlstra A, Rubin MA, Di Vizio D (2017b) Extracellular vesicles for liquid biopsy in prostate cancer: where are we and where are we headed? Prostate Cancer Prostatic Dis 20:251–258CrossRefPubMedPubMedCentralGoogle Scholar
  45. Misra UK, Gawdi G, Pizzo SV (1995) Ligation of the alpha 2-macroglobulin signalling receptor on macrophages induces protein phosphorylation and an increase in cytosolic pH. Biochem J 309:151–158CrossRefPubMedPubMedCentralGoogle Scholar
  46. Misra UK, Gawdi G, Pizzo SV (1999) Ligation of low-density lipoprotein receptor-related protein with antibodies elevates intracellular calcium and inositol 1,4, 5-trisphosphate in macrophages. Arch Biochem Biophys 372:238–247CrossRefGoogle Scholar
  47. Nagaraju GP, Long TE, Park W, Landry JC, Taliaferro-Smith L, Farris AB, Diaz R, El-Rayes BF (2015) Heat shock protein 90 promotes epithelial to mesenchymal transition, invasion, and migration in colorectal cancer. Mol Carcinog 54:1147–1158CrossRefPubMedPubMedCentralGoogle Scholar
  48. Najafi M, Goradel NH, Farhood B, Salehi E, Solhjoo S, Toolee H, Kharazinejad E, Mortezaee K (2019) Tumor microenvironment: interactions and therapy. J Cell Physiol 234:5700–5721CrossRefGoogle Scholar
  49. Nakase I, Kobayashi NB, Takatani-Nakase T, Yoshida T (2015) Active macropinocytosis induction by stimulation of epidermal growth factor receptor and oncogenic Ras expression potentiates cellular uptake efficacy of exosomes. Sci Rep 5:10300CrossRefPubMedPubMedCentralGoogle Scholar
  50. Namba Y, Sogawa C, Okusha Y, al e (2018) Depletion of lipid efflux pump ABCG1 triggers the intracellular accumulation of extracellular vesicles and reduces aggregation and tumorigenesis of metastatic cancer cells. Front Oncol 8:376CrossRefPubMedPubMedCentralGoogle Scholar
  51. Nashida T, Imai A, Shimomura H (2006) Relation of Rab26 to the amylase release from rat parotid acinar cells. Arch Oral Biol 51:89–95CrossRefPubMedPubMedCentralGoogle Scholar
  52. Neckers L, Blagg B, Haystead T, Trepel JB, Whitesell L, Picard D (2018) Methods to validate Hsp90 inhibitor specificity, to identify off-target effects, and to rethink approaches for further clinical development. Cell Stress Chaperones 23:467–482CrossRefPubMedPubMedCentralGoogle Scholar
  53. Nolan KD, Franco OE, Hance MW, Hayward SW, Isaacs JS (2015) Tumor-secreted Hsp90 subverts polycomb function to drive prostate tumor growth and invasion. J Biol Chem 290:8271–8282CrossRefPubMedPubMedCentralGoogle Scholar
  54. Nolan KD, Kaur J, Isaacs JS (2017) Secreted heat shock protein 90 promotes prostate cancer stem cell heterogeneity. Oncotarget 8:19323–19341CrossRefPubMedPubMedCentralGoogle Scholar
  55. Ono K, Eguchi T, Sogawa C, Calderwood SK, Futagawa J, Kasai T, Seno M, Okamoto K, Sasaki A, Kozaki KI (2018) HSP-enriched properties of extracellular vesicles involve survival of metastatic oral cancer cells. J Cell Biochem 119:7363–7376CrossRefGoogle Scholar
  56. Peinado H, Lavotshkin S, Lyden D (2011) The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts. Semin Cancer Biol 21:139–146CrossRefPubMedPubMedCentralGoogle Scholar
  57. Pereira-Leal JB, Seabra MC (2000) The mammalian Rab family of small GTPases: definition of family and subfamily sequence motifs suggests a mechanism for functional specificity in the Ras superfamily. J Mol Biol 301:1077–1087CrossRefPubMedPubMedCentralGoogle Scholar
  58. Purushothaman A, Bandari SK, Liu J, Mobley JA, Brown EE, Sanderson RD (2016) Fibronectin on the surface of myeloma cell-derived exosomes mediates exosome-cell interactions. J Biol Chem 291:1652–1663CrossRefGoogle Scholar
  59. Roy A, Coum A, Marinescu VD, Polajeva J, Smits A, Nelander S, Uhrbom L, Westermark B, Forsberg-Nilsson K, Ponten F, Tchougounova E (2015) Glioma-derived plasminogen activator inhibitor-1 (PAI-1) regulates the recruitment of LRP1 positive mast cells. Oncotarget 6:23647–23661CrossRefPubMedPubMedCentralGoogle Scholar
  60. Rupnik M, Kreft M, Nothias F, Grilc S, Bobanovic LK, Johannes L, Kiauta T, Vernier P, Darchen F, Zorec R (2007) Distinct role of Rab3A and Rab3B in secretory activity of rat melanotrophs. Am J Phys Cell Phys 292:C98–C105CrossRefGoogle Scholar
  61. Savina A, Vidal M, Colombo MI (2002) The exosome pathway in K562 cells is regulated by Rab11. J Cell Sci 115:2505–2515PubMedGoogle Scholar
  62. Shimada-Sugawara M, Sakai E, Okamoto K, Fukuda M, Izumi T, Yoshida N, Tsukuba T (2015) Rab27A regulates transport of cell surface receptors modulating multinucleation and lysosome-related organelles in osteoclasts. Sci Rep 5:9620CrossRefPubMedPubMedCentralGoogle Scholar
  63. Shimo T, Kubota S, Yoshioka N, Ibaragi S, Isowa S, Eguchi T, Sasaki A, Takigawa M (2006) Pathogenic role of connective tissue growth factor (CTGF/CCN2) in osteolytic metastasis of breast cancer. J Bone Miner Res 21:1045–1059CrossRefPubMedGoogle Scholar
  64. Stenmark H (2009) Rab GTPases as coordinators of vesicle traffic. Nat Rev Mol Cell Biol 10:513–525CrossRefPubMedGoogle Scholar
  65. Sung BH, Ketova T, Hoshino D, Zijlstra A, Weaver AM (2015) Directional cell movement through tissues is controlled by exosome secretion. Nat Commun 6:7164CrossRefPubMedPubMedCentralGoogle Scholar
  66. Takahashi S, Kubo K, Waguri S, Yabashi A, Shin HW, Katoh Y, Nakayama K (2012) Rab11 regulates exocytosis of recycling vesicles at the plasma membrane. J Cell Sci 125:4049–4057CrossRefPubMedPubMedCentralGoogle Scholar
  67. Taverna S, Pucci M, Giallombardo M, Di Bella MA, Santarpia M, Reclusa P, Gil-Bazo I, Rolfo C, Alessandro R (2017) Amphiregulin contained in NSCLC-exosomes induces osteoclast differentiation through the activation of EGFR pathway. Sci Rep 7:3170CrossRefPubMedPubMedCentralGoogle Scholar
  68. Tolmachova T, Abrink M, Futter CE, Authi KS, Seabra MC (2007) Rab27b regulates number and secretion of platelet dense granules. Proc Natl Acad Sci U S A 104:5872–5877CrossRefPubMedPubMedCentralGoogle Scholar
  69. Tsen F, Bhatia A, O’Brien K, Cheng CF, Chen M, Hay N, Stiles B, Woodley DT, Li W (2013) Extracellular heat shock protein 90 signals through subdomain II and the NPVY motif of LRP-1 receptor to Akt1 and Akt2: a circuit essential for promoting skin cell migration in vitro and wound healing in vivo. Mol Cell Biol 33:4947–4959CrossRefPubMedPubMedCentralGoogle Scholar
  70. Ueda K, Ishikawa N, Tatsuguchi A, Saichi N, Fujii R, Nakagawa H (2014) Antibody-coupled monolithic silica microtips for highthroughput molecular profiling of circulating exosomes. Sci Rep 4:6232CrossRefPubMedPubMedCentralGoogle Scholar
  71. van Niel G (2016) Study of exosomes shed new light on physiology of amyloidogenesis. Cell Mol Neurobiol 36:327–342CrossRefGoogle Scholar
  72. Wasmeier C, Romao M, Plowright L, Bennett DC, Raposo G, Seabra MC (2006) Rab38 and Rab32 control post-Golgi trafficking of melanogenic enzymes. J Cell Biol 175:271–281CrossRefPubMedPubMedCentralGoogle Scholar
  73. Willnow TE, Hammes A, Eaton S (2007) Lipoproteins and their receptors in embryonic development: more than cholesterol clearance. Development 134:3239–3249CrossRefGoogle Scholar
  74. Yamaguchi Y, Sakai E, Okamoto K, Kajiya H, Okabe K, Naito M, Kadowaki T, Tsukuba T (2018) Rab44, a novel large Rab GTPase, negatively regulates osteoclast differentiation by modulating intracellular calcium levels followed by NFATc1 activation. Cell Mol Life Sci 75:33–48CrossRefGoogle Scholar
  75. Yang T, Williams BO (2017) Low-density lipoprotein receptor-related proteins in skeletal development and disease. Physiol Rev 97:1211–1228CrossRefPubMedPubMedCentralGoogle Scholar
  76. Zhang H, Freitas D, Kim HS, Fabijanic K, Li Z, Chen H, Mark MT, Molina H, Martin AB, Bojmar L, Fang J, Rampersaud S, Hoshino A, Matei I, Kenific CM, Nakajima M, Mutvei AP, Sansone P, Buehring W, Wang H, Jimenez JP, Cohen-Gould L, Paknejad N, Brendel M, Manova-Todorova K, Magalhaes A, Ferreira JA, Osorio H, Silva AM, Massey A, Cubillos-Ruiz JR, Galletti G, Giannakakou P, Cuervo AM, Blenis J, Schwartz R, Brady MS, Peinado H, Bromberg J, Matsui H, Reis CA, Lyden D (2018) Identification of distinct nanoparticles and subsets of extracellular vesicles by asymmetric flow field-flow fractionation. Nat Cell Biol 20:332–343CrossRefPubMedPubMedCentralGoogle Scholar
  77. Zheng Y, Campbell EC, Lucocq J, Riches A, Powis SJ (2013) Monitoring the Rab27 associated exosome pathway using nanoparticle tracking analysis. Exp Cell Res 319:1706–1713CrossRefGoogle Scholar
  78. Zijlstra A, Di Vizio D (2018) Size matters in nanoscale communication. Nat Cell Biol 20:228–230CrossRefPubMedPubMedCentralGoogle Scholar
  79. Zilberberg A, Yaniv A, Gazit A (2004) The low density lipoprotein receptor-1, LRP1, interacts with the human frizzled-1 (HFz1) and down-regulates the canonical Wnt signaling pathway. J Biol Chem 279:17535–17542CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Takanori Eguchi
    • 1
    • 2
    Email author
  • Kisho Ono
    • 1
    • 3
  • Kazumi Kawata
    • 4
  • Kuniaki Okamoto
    • 1
  • Stuart K. Calderwood
    • 5
  1. 1.Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayama UniversityOkayamaJapan
  2. 2.Advanced Research Center for Oral and Craniofacial Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayama UniversityOkayamaJapan
  3. 3.Department of Oral and Maxillofacial SurgeryOkayama University HospitalOkayamaJapan
  4. 4.Department of Biochemistry and Molecular Dentistry, Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayama UniversityOkayamaJapan
  5. 5.Department of Radiation Oncology, Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonUSA

Personalised recommendations