Heat Shock Protein 70 (Hsp70) in the Regulation of Platelet Function

  • Rachel A. Rigg
  • Owen J. T. McCarty
  • Joseph E. Aslan
Part of the Heat Shock Proteins book series (HESP, volume 13)


Heat shock protein 70 (Hsp70) and its family of molecular chaperones are critical mediators of protein folding, trafficking, and control. Platelets are known to express several members of the Hsp70 family at high levels, suggesting critical roles for Hsp70 in platelet function. Several studies have described Hsp70-associated activities in intracellular signaling events, including the regulation of the linker for activation of T cells (LAT) signalosome that initiates integrin conformational changes underlying platelet aggregation. Although other chaperones perform established extracellular functions on the platelet surface as well as in the circulation to mediate the activities of platelets and other hematopoietic cells in hemostasis, thrombosis, and inflammation, similar roles for Hsp70 in platelet regulation remain undefined. Given the extensive roles of Hsp70 in many platelet-related human disease states, from protective roles in cardiovascular disease and wound healing to pathological roles in cancer, inflammation, and metabolic diseases, the emerging importance of Hsp70 in platelet function offers numerous ramifications for human health and disease.


Chaperones Hemostasis Inflammation Integrin Platelets Thrombosis 



Adenosine diphosphate


Activated protein C


Adenosine triphosphate


C-type lectin


Collagen-related peptide


Endoplasmic reticulum


G-protein coupled receptor


Glycoprotein VI


Glucose-regulated protein


Guanosine triphosphate


Heat shock protein


Integrin-linked kinase


Linker for activation of T cells


Nucleotide exchange factor


Protease-activated receptor


Protein disulfide isomerase




Phospholipase C


Receptor for advanced glycation endproducts


Toll-like receptor


Thrombin receptor-activating peptide-6


Thromboxane A2



The authors thank the Knight Cardiovascular Institute, the National Institutes of Health (R01HL101972 and R01GM116184 to O.J.T.M.), and the American Heart Association (17SDG33350075 to J.E.A. and 13EIA12630000 to O.J.T.M.) for support.


The authors have no conflicts of interest to declare.


  1. Allende, M., Molina, E., Guruceaga, E., Tamayo, I., Gonzalez-Porras, J. R., Gonzalez-Lopez, T. J., Toledo, E., Rabal, O., Ugarte, A., Roldan, V., Rivera, J., Oyarzabal, J., Montes, R., & Hermida, J. (2016). Hsp70 protects from stroke in atrial fibrillation patients by preventing thrombosis without increased bleeding risk. Cardiovascular Research, 110, 309–318.PubMedCrossRefGoogle Scholar
  2. Allende, M., Molina, E., Lecumberri, R., Sanchez-Arias, J. A., Ugarte, A., Guruceaga, E., Oyarzabal, J., & Hermida, J. (2017). Inducing heat shock protein 70 expression provides a robust antithrombotic effect with minimal bleeding risk. Thrombosis and Haemostasis, 117, 1722.PubMedCrossRefGoogle Scholar
  3. Anand, P. K. (2010). Exosomal membrane molecules are potent immune response modulators. Communicative & Integrative Biology, 3, 405–408.CrossRefGoogle Scholar
  4. Asea, A., Kraeft, S. K., Kurt-Jones, E. A., Stevenson, M. A., Chen, L. B., Finberg, R. W., Koo, G. C., & Calderwood, S. K. (2000). HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nature Medicine, 6, 435–442.PubMedCrossRefGoogle Scholar
  5. Asea, A., Rehli, M., Kabingu, E., Boch, J. A., Bare, O., Auron, P. E., Stevenson, M. A., & Calderwood, S. K. (2002). Novel signal transduction pathway utilized by extracellular HSP70: Role of toll-like receptor (TLR) 2 and TLR4. The Journal of Biological Chemistry, 277, 15028–15034.PubMedCrossRefGoogle Scholar
  6. Aslam, R., Speck, E. R., Kim, M., Crow, A. R., Bang, K. W., Nestel, F. P., Ni, H., Lazarus, A. H., Freedman, J., & Semple, J. W. (2006). Platelet toll-like receptor expression modulates lipopolysaccharide-induced thrombocytopenia and tumor necrosis factor-alpha production in vivo. Blood, 107, 637–641.PubMedCrossRefGoogle Scholar
  7. Aslan, J. E. (2017). Platelet shape change. In P. Gresele, N. S. Kleiman, J. A. Lopez, & C. P. Page (Eds.), Platelets in thrombotic and non-thrombotic disorders: Pathophysiology, pharmacology and therapeutics: An update (pp. 321–336). Cham: Springer.CrossRefGoogle Scholar
  8. Aslan, J. E., Itakura, A., Gertz, J. M., & McCarty, O. J. (2012). Platelet shape change and spreading. Methods in Molecular Biology, 788, 91–100.PubMedCrossRefGoogle Scholar
  9. Aslan, J. E., Rigg, R. A., Nowak, M. S., Loren, C. P., Baker-Groberg, S. M., Pang, J., David, L. L., & McCarty, O. J. (2015). Lysine acetyltransfer supports platelet function. Journal of Thrombosis and Haemostasis, 13, 1908–1917.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Assimon, V. A., Gillies, A. T., Rauch, J. N., & Gestwicki, J. E. (2013). Hsp70 protein complexes as drug targets. Current Pharmaceutical Design, 19, 404–417.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Atalay, M., Oksala, N., Lappalainen, J., Laaksonen, D. E., Sen, C. K., & Roy, S. (2009). Heat shock proteins in diabetes and wound healing. Current Protein & Peptide Science, 10, 85–95.CrossRefGoogle Scholar
  12. Bellaye, P. S., Burgy, O., Causse, S., Garrido, C., & Bonniaud, P. (2014). Heat shock proteins in fibrosis and wound healing: Good or evil? Pharmacology & Therapeutics, 143, 119–132.CrossRefGoogle Scholar
  13. Bertolotti, A., Zhang, Y., Hendershot, L. M., Harding, H. P., & Ron, D. (2000). Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nature Cell Biology, 2, 326–332.PubMedCrossRefGoogle Scholar
  14. Boorstein, W. R., Ziegelhoffer, T., & Craig, E. A. (1994). Molecular evolution of the HSP70 multigene family. Journal of Molecular Evolution, 38, 1–17.PubMedCrossRefGoogle Scholar
  15. Broos, K., Feys, H. B., De Meyer, S. F., Vanhoorelbeke, K., & Deckmyn, H. (2011). Platelets at work in primary hemostasis. Blood Reviews, 25, 155–167.PubMedCrossRefGoogle Scholar
  16. Burkhart, J. M., Vaudel, M., Gambaryan, S., Radau, S., Walter, U., Martens, L., Geiger, J., Sickmann, A., & Zahedi, R. P. (2012). The first comprehensive and quantitative analysis of human platelet protein composition allows the comparative analysis of structural and functional pathways. Blood, 120, e73–e82.PubMedCrossRefGoogle Scholar
  17. Chan, Y. C., Greenwood, D. R., Yang, Y., Leung, E., & Krissansen, G. W. (2015). Leukocyte integrin α4β7 associates with heat shock protein 70. Molecular and Cellular Biochemistry, 409(1–2), 263–269.PubMedCrossRefGoogle Scholar
  18. Chen, T., & Cao, X. (2010). Stress for maintaining memory: HSP70 as a mobile messenger for innate and adaptive immunity. European Journal of Immunology, 40, 1541–1544.PubMedCrossRefGoogle Scholar
  19. Chen, Z., Xu, L., Su, T., Ke, Z., Peng, Z., Zhang, N., Peng, S., Zhang, Q., Liu, G., Wei, G., Guo, Y., He, M., & Kuang, M. (2017). Autocrine STIP1 signaling promotes tumor growth and is associated with disease outcome in hepatocellular carcinoma. Biochemical and Biophysical Research Communications, 493(1), 365–372.PubMedCrossRefGoogle Scholar
  20. Cho, J., Kennedy, D. R., Lin, L., Huang, M., Merrill-Skoloff, G., Furie, B. C., & Furie, B. (2012). Protein disulfide isomerase capture during thrombus formation in vivo depends on the presence of beta3 integrins. Blood, 120, 647–655.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Clerico, E. M., Tilitsky, J. M., Meng, W., & Gierasch, L. M. (2015). How Hsp70 molecular machines interact with their substrates to mediate diverse physiological functions. Journal of Molecular Biology, 427, 1575–1588.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Colvin, T. A., Gabai, V. L., Gong, J., Calderwood, S. K., Li, H., Gummuluru, S., Matchuk, O. N., Smirnova, S. G., Orlova, N. V., Zamulaeva, I. A., Garcia-Marcos, M., Li, X., Young, Z. T., Rauch, J. N., Gestwicki, J. E., Takayama, S., & Sherman, M. Y. (2014). Hsp70-Bag3 interactions regulate cancer-related signaling networks. Cancer Research, 74, 4731–4740.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Crescente, M., Pluthero, F. G., Li, L., Lo, R. W., Walsh, T. G., Schenk, M. P., Holbrook, L. M., Louriero, S., Ali, M. S., Vaiyapuri, S., Falet, H., Jones, I. M., Poole, A. W., Kahr, W. H., & Gibbins, J. M. (2016). Intracellular trafficking, localization, and mobilization of platelet-borne thiol isomerases. Arteriosclerosis, Thrombosis, and Vascular Biology, 36, 1164–1173.PubMedPubMedCentralCrossRefGoogle Scholar
  24. Delom, F., Mallet, B., Carayon, P., & Lejeune, P. J. (2001). Role of extracellular molecular chaperones in the folding of oxidized proteins. Refolding of colloidal thyroglobulin by protein disulfide isomerase and immunoglobulin heavy chain-binding protein. The Journal of Biological Chemistry, 276, 21337–21342.PubMedCrossRefGoogle Scholar
  25. Duerschmied, D., & Bode, C. (2016). Hsp70 preventing thrombosis: Benefit without burden? Cardiovascular Research, 110, 291–292.PubMedCrossRefGoogle Scholar
  26. Durrant, T. N., Hutchinson, J. L., Heesom, K. J., Anderson, K. E., Stephens, L. R., Hawkins, P. T., Marshall, A. J., Moore, S. F., & Hers, I. (2017). In-depth PtdIns(3,4,5)P3 signalosome analysis identifies DAPP1 as a negative regulator of GPVI-driven platelet function. Blood Advances, 1, 918–932.PubMedPubMedCentralCrossRefGoogle Scholar
  27. Furie, B., & Flaumenhaft, R. (2014). Thiol isomerases in thrombus formation. Circulation Research, 114, 1162–1173.PubMedPubMedCentralCrossRefGoogle Scholar
  28. Galovic, R., Flegar-Mestric, Z., Vidjak, V., Matokanovic, M., & Barisic, K. (2016). Heat shock protein 70 and antibodies to heat shock protein 60 are associated with cerebrovascular atherosclerosis. Clinical Biochemistry, 49, 66–69.PubMedCrossRefGoogle Scholar
  29. Gerthoffer, W. T., & Gunst, S. J. (2001). Invited review: Focal adhesion and small heat shock proteins in the regulation of actin remodeling and contractility in smooth muscle. Journal of Applied Physiology (1985), 91, 963–972.CrossRefGoogle Scholar
  30. Gibbins, J. M. (2013). Platelets using proteins creatively. Blood, 122, 3553–3554.PubMedCrossRefGoogle Scholar
  31. Golebiewska, E. M., & Poole, A. W. (2015). Platelet secretion: From haemostasis to wound healing and beyond. Blood Reviews, 29, 153–162.PubMedPubMedCentralCrossRefGoogle Scholar
  32. Gros, A., Ollivier, V., & Ho-Tin-Noe, B. (2014). Platelets in inflammation: Regulation of leukocyte activities and vascular repair. Frontiers in Immunology, 5, 678.PubMedGoogle Scholar
  33. Gutierrez, T., & Simmen, T. (2014). Endoplasmic reticulum chaperones and oxidoreductases: Critical regulators of tumor cell survival and immunorecognition. Frontiers in Oncology, 4, 291.PubMedPubMedCentralGoogle Scholar
  34. Hansen, G. A., Ludvigsen, M., Jacobsen, C., Cangemi, C., Rasmussen, L. M., Vorum, H., & Honore, B. (2015). Fibulin-1C, C1 esterase inhibitor and glucose regulated protein 75 interact with the CREC proteins, calumenin and Reticulocalbin. PLoS One, 10, e0132283.PubMedCrossRefGoogle Scholar
  35. Hartl, F. U., Bracher, A., & Hayer-Hartl, M. (2011). Molecular chaperones in protein folding and proteostasis. Nature, 475, 324–332.PubMedCrossRefPubMedCentralGoogle Scholar
  36. Hilf, N., Singh-Jasuja, H., Schwarzmaier, P., Gouttefangeas, C., Rammensee, H. G., & Schild, H. (2002). Human platelets express heat shock protein receptors and regulate dendritic cell maturation. Blood, 99, 3676–3682.PubMedCrossRefGoogle Scholar
  37. Hughes, C. E., Auger, J. M., McGlade, J., Eble, J. A., Pearce, A. C., & Watson, S. P. (2008). Differential roles for the adapters gads and LAT in platelet activation by GPVI and CLEC-2. Journal of Thrombosis and Haemostasis, 6, 2152–2159.PubMedPubMedCentralCrossRefGoogle Scholar
  38. Hutter, J. J., Mestril, R., Tam, E. K., Sievers, R. E., Dillmann, W. H., & Wolfe, C. L. (1996). Overexpression of heat shock protein 72 in transgenic mice decreases infarct size in vivo. Circulation, 94, 1408–1411.PubMedCrossRefGoogle Scholar
  39. Inoue, N., & Sawamura, T. (2007). Lectin-like oxidized LDL receptor-1 as extracellular chaperone receptor: Its versatile functions and human diseases. Methods, 43, 218–222.PubMedCrossRefGoogle Scholar
  40. Inwald, D. P., McDowall, A., Peters, M. J., Callard, R. E., & Klein, N. J. (2003). CD40 is constitutively expressed on platelets and provides a novel mechanism for platelet activation. Circulation Research, 92, 1041–1048.PubMedCrossRefGoogle Scholar
  41. Jang, J., Kim, M. R., Kim, T. K., Lee, W. R., Kim, J. H., Heo, K., & Lee, S. (2017). CLEC14a-HSP70-1A interaction regulates HSP70-1A-induced angiogenesis. Scientific Reports, 7(10666), 10666.PubMedPubMedCentralCrossRefGoogle Scholar
  42. Kabbage, M., & Dickman, M. B. (2008). The BAG proteins: A ubiquitous family of chaperone regulators. Cellular and Molecular Life Sciences, 65, 1390–1402.PubMedCrossRefGoogle Scholar
  43. Kageyama, Y., Doi, T., Akamatsu, S., Kuroyanagi, G., Kondo, A., Mizutani, J., Otsuka, T., Tokuda, H., Kozawa, O., & Ogura, S. (2013). Rac regulates collagen-induced HSP27 phosphorylation via p44/p42 MAP kinase in human platelets. International Journal of Molecular Medicine, 32, 813–818.PubMedCrossRefGoogle Scholar
  44. Kaiser, W. J., Holbrook, L. M., Tucker, K. L., Stanley, R. G., & Gibbins, J. M. (2009). A functional proteomic method for the enrichment of peripheral membrane proteins reveals the collagen binding protein Hsp47 is exposed on the surface of activated human platelets. Journal of Proteome Research, 8, 2903–2914.PubMedCrossRefGoogle Scholar
  45. Kampinga, H. H., & Craig, E. A. (2010). The HSP70 chaperone machinery: J proteins as drivers of functional specificity. Nature Reviews. Molecular Cell Biology, 11, 579–592.PubMedPubMedCentralCrossRefGoogle Scholar
  46. Kato, H., Takai, S., Matsushima-Nishiwaki, R., Adachi, S., Minamitani, C., Otsuka, T., Tokuda, H., Akamatsu, S., Doi, T., Ogura, S., & Kozawa, O. (2008). HSP27 phosphorylation is correlated with ADP-induced platelet granule secretion. Archives of Biochemistry and Biophysics, 475, 80–86.PubMedCrossRefGoogle Scholar
  47. Kim, T. K., Na, H. J., Lee, W. R., Jeoung, M. H., & Lee, S. (2016). Heat shock protein 70-1A is a novel angiogenic regulator. Biochemical and Biophysical Research Communications, 469, 222–228.PubMedCrossRefGoogle Scholar
  48. Krause, M., Heck, T. G., Bittencourt, A., Scomazzon, S. P., Newsholme, P., Curi, R., Homem de Bittencourt, P. I., & Jr. (2015). The chaperone balance hypothesis: The importance of the extracellular to intracellular HSP70 ratio to inflammation-driven type 2 diabetes, the effect of exercise, and the implications for clinical management. Mediators of Inflammation, 2015, 249205.PubMedPubMedCentralCrossRefGoogle Scholar
  49. Krepuska, M., Szeberin, Z., Sotonyi, P., Sarkadi, H., Fehervari, M., Apor, A., Rimely, E., Prohaszka, Z., & Acsady, G. (2011). Serum level of soluble Hsp70 is associated with vascular calcification. Cell Stress & Chaperones, 16, 257–265.CrossRefGoogle Scholar
  50. Kruse, D. E., Mackanos, M. A., O’Connell-Rodwell, C. E., Contag, C. H., & Ferrara, K. W. (2008). Short-duration-focused ultrasound stimulation of Hsp70 expression in vivo. Physics in Medicine and Biology, 53, 3641–3660.PubMedPubMedCentralCrossRefGoogle Scholar
  51. Lalo, U., Jones, S., Roberts, J. A., Mahaut-Smith, M. P., & Evans, R. J. (2012). Heat shock protein 90 inhibitors reduce trafficking of ATP-gated P2X1 receptors and human platelet responsiveness. The Journal of Biological Chemistry, 287, 32747–32754.PubMedPubMedCentralCrossRefGoogle Scholar
  52. Lancaster, G. I., & Febbraio, M. A. (2005). Exosome-dependent trafficking of HSP70: A novel secretory pathway for cellular stress proteins. The Journal of Biological Chemistry, 280, 23349–23355.PubMedCrossRefGoogle Scholar
  53. Ma, C., Yao, Y., Yue, Q. X., Zhou, X. W., Yang, P. Y., Wu, W. Y., Guan, S. H., Jiang, B. H., Yang, M., Liu, X., & Guo, D. A. (2011). Differential proteomic analysis of platelets suggested possible signal cascades network in platelets treated with salvianolic acid B. PLoS One, 6, e14692.PubMedPubMedCentralCrossRefGoogle Scholar
  54. Mambula, S. S., Stevenson, M. A., Ogawa, K., & Calderwood, S. K. (2007). Mechanisms for Hsp70 secretion: Crossing membranes without a leader. Methods, 43, 168–175.PubMedPubMedCentralCrossRefGoogle Scholar
  55. Massey, A. J., Williamson, D. S., Browne, H., Murray, J. B., Dokurno, P., Shaw, T., Macias, A. T., Daniels, Z., Geoffroy, S., Dopson, M., Lavan, P., Matassova, N., Francis, G. L., Graham, C. J., Parsons, R., Wang, Y., Padfield, A., Comer, M., Drysdale, M. J., & Wood, M. (2010). A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells. Cancer Chemotherapy and Pharmacology, 66, 535–545.PubMedCrossRefGoogle Scholar
  56. Mateos-Caceres, P. J., Macaya, C., Azcona, L., Modrego, J., Mahillo, E., Bernardo, E., Fernandez-Ortiz, A., & Lopez-Farre, A. J. (2010). Different expression of proteins in platelets from aspirin-resistant and aspirin-sensitive patients. Thrombosis and Haemostasis, 103, 160–170.PubMedCrossRefGoogle Scholar
  57. Mayer, M. P., & Bukau, B. (2005). Hsp70 chaperones: Cellular functions and molecular mechanism. Cellular and Molecular Life Sciences, 62, 670–684.PubMedPubMedCentralCrossRefGoogle Scholar
  58. Molins, B., Pena, E., Padro, T., Casani, L., Mendieta, C., & Badimon, L. (2010). Glucose-regulated protein 78 and platelet deposition: Effect of rosuvastatin. Arteriosclerosis, Thrombosis, and Vascular Biology, 30, 1246–1252.PubMedCrossRefGoogle Scholar
  59. Molvarec, A., Tamasi, L., Losonczy, G., Madach, K., Prohaszka, Z., & Rigo, J.,. J. (2010). Circulating heat shock protein 70 (HSPA1A) in normal and pathological pregnancies. Cell Stress & Chaperones, 15, 237–247.CrossRefGoogle Scholar
  60. Nollen, E. A., & Morimoto, R. I. (2002). Chaperoning signaling pathways: Molecular chaperones as stress-sensing ‘heat shock’ proteins. Journal of Cell Science, 115, 2809–2816.PubMedGoogle Scholar
  61. Pasquet, J. M., Gross, B., Quek, L., Asazuma, N., Zhang, W., Sommers, C. L., Schweighoffer, E., Tybulewicz, V., Judd, B., Lee, J. R., Koretzky, G., Love, P. E., Samelson, L. E., & Watson, S. P. (1999). LAT is required for tyrosine phosphorylation of phospholipase cgamma2 and platelet activation by the collagen receptor GPVI. Molecular and Cellular Biology, 19, 8326–8334.PubMedPubMedCentralCrossRefGoogle Scholar
  62. Passam, F. H., Lin, L., Gopal, S., Stopa, J. D., Bellido-Martin, L., Huang, M., Furie, B. C., & Furie, B. (2015). Both platelet- and endothelial cell-derived ERp5 support thrombus formation in a laser-induced mouse model of thrombosis. Blood, 125, 2276–2285.PubMedPubMedCentralCrossRefGoogle Scholar
  63. Patury, S., Miyata, Y., & Gestwicki, J. E. (2009). Pharmacological targeting of the Hsp70 chaperone. Current Topics in Medicinal Chemistry, 9, 1337–1351.PubMedPubMedCentralCrossRefGoogle Scholar
  64. Pichon, S., Bryckaert, M., & Berrou, E. (2004). Control of actin dynamics by p38 MAP kinase - Hsp27 distribution in the lamellipodium of smooth muscle cells. Journal of Cell Science, 117, 2569–2577.PubMedCrossRefGoogle Scholar
  65. Pockley, A. G., Calderwood, S. K., & Multhoff, G. (2009). The atheroprotective properties of Hsp70: A role for Hsp70-endothelial interactions? Cell Stress & Chaperones, 14, 545–553.CrossRefGoogle Scholar
  66. Polanowska-Grabowska, R., Simon, C. G., Jr., Falchetto, R., Shabanowitz, J., Hunt, D. F., & Gear, A. R. (1997). Platelet adhesion to collagen under flow causes dissociation of a phosphoprotein complex of heat-shock proteins and protein phosphatase 1. Blood, 90, 1516–1526.PubMedGoogle Scholar
  67. Pratt, W. B., & Toft, D. O. (2003). Regulation of signaling protein function and trafficking by the hsp90/hsp70-based chaperone machinery. Experimental Biology and Medicine (Maywood), 228, 111–133.CrossRefGoogle Scholar
  68. Rigg, R. A., Healy, L. D., Nowak, M. S., Mallet, J., Thierheimer, M. L., Pang, J., McCarty, O. J., & Aslan, J. E. (2016). Heat shock protein 70 regulates platelet integrin activation, granule secretion and aggregation. American Journal of Physiology. Cell Physiology, 310, C568–C575.PubMedPubMedCentralCrossRefGoogle Scholar
  69. Rodrigues-Krause, J., Krause, M., O'Hagan, C., De Vito, G., Boreham, C., Murphy, C., Newsholme, P., & Colleran, G. (2012). Divergence of intracellular and extracellular HSP72 in type 2 diabetes: Does fat matter? Cell Stress & Chaperones, 17, 293–302.CrossRefGoogle Scholar
  70. Rondina, M. T., Weyrich, A. S., & Zimmerman, G. A. (2013). Platelets as cellular effectors of inflammation in vascular diseases. Circulation Research, 112, 1506–1519.PubMedPubMedCentralCrossRefGoogle Scholar
  71. Rousaki, A., Miyata, Y., Jinwal, U. K., Dickey, C. A., Gestwicki, J. E., & Zuiderweg, E. R. (2011). Allosteric drugs: The interaction of antitumor compound MKT-077 with human Hsp70 chaperones. Journal of Molecular Biology, 411, 614–632.PubMedPubMedCentralCrossRefGoogle Scholar
  72. Roy, S., Sun, A., & Redman, C. (1996). In vitro assembly of the component chains of fibrinogen requires endoplasmic reticulum factors. The Journal of Biological Chemistry, 271, 24544–24550.PubMedCrossRefGoogle Scholar
  73. Saibil, H. (2013). Chaperone machines for protein folding, unfolding and disaggregation. Nature Reviews. Molecular Cell Biology, 14, 630–642.PubMedPubMedCentralCrossRefGoogle Scholar
  74. Santos, T. M., Sinzato, Y. K., Gallego, F. Q., Iessi, I. L., Volpato, G. T., Dallaqua, B., & Damasceno, D. C. (2015). Extracellular HSP70 levels in diabetic environment in rats. Cell Stress & Chaperones, 20, 595–603.CrossRefGoogle Scholar
  75. Schaletzki, Y., Kromrey, M. L., Broderdorf, S., Hammer, E., Grube, M., Hagen, P., Sucic, S., Freissmuth, M., Volker, U., Greinacher, A., Rauch, B. H., Kroemer, H. K., & Jedlitschky, G. (2017). Several adaptor proteins promote intracellular localisation of the transporter MRP4/ABCC4 in platelets and haematopoietic cells. Thrombosis and Haemostasis, 117, 105–115.PubMedCrossRefGoogle Scholar
  76. Schlecht, R., Scholz, S. R., Dahmen, H., Wegener, A., Sirrenberg, C., Musil, D., Bomke, J., Eggenweiler, H. M., Mayer, M. P., & Bukau, B. (2013). Functional analysis of Hsp70 inhibitors. PLoS One, 8, e78443.PubMedPubMedCentralCrossRefGoogle Scholar
  77. Schulman, S., Bendapudi, P., Sharda, A., Chen, V., Bellido-Martin, L., Jasuja, R., Furie, B. C., Flaumenhaft, R., & Furie, B. (2016). Extracellular thiol isomerases and their role in thrombus formation. Antioxidants & Redox Signaling, 24, 1–15.CrossRefGoogle Scholar
  78. Shiraki, R., Inoue, N., Kawasaki, S., Takei, A., Kadotani, M., Ohnishi, Y., Ejiri, J., Kobayashi, S., Hirata, K., Kawashima, S., & Yokoyama, M. (2004). Expression of toll-like receptors on human platelets. Thrombosis Research, 113, 379–385.PubMedCrossRefGoogle Scholar
  79. Smyth, S. S., McEver, R. P., Weyrich, A. S., Morrell, C. N., Hoffman, M. R., Arepally, G. M., French, P. A., Dauerman, H. L., & Becker, R. C. (2009). Platelet functions beyond hemostasis. Journal of Thrombosis and Haemostasis, 7, 1759–1766.PubMedCrossRefGoogle Scholar
  80. Somensi, N., Brum, P. O., de Miranda Ramos, V., Gasparotto, J., Zanotto-Filho, A., Rostirolla, D. C., da Silva Morrone, M., Moreira, J. C. F., & Pens Gelain, D. (2017). Extracellular HSP70 activates ERK1/2, NF-kB and pro-inflammatory gene transcription through binding with RAGE in A549 human lung cancer cells. Cellular Physiology and Biochemistry, 42, 2507–2522.PubMedCrossRefGoogle Scholar
  81. Staron, M., Wu, S., Hong, F., Stojanovic, A., Du, X., Bona, R., Liu, B., & Li, Z. (2011). Heat-shock protein gp96/grp94 is an essential chaperone for the platelet glycoprotein Ib-IX-V complex. Blood, 117, 7136–7144.PubMedPubMedCentralCrossRefGoogle Scholar
  82. Sturner, E., & Behl, C. (2017). The role of the multifunctional BAG3 protein in cellular protein quality control and in disease. Frontiers in Molecular Neuroscience, 10, 177.PubMedPubMedCentralCrossRefGoogle Scholar
  83. Suttitanamongkol, S., Polanowska-Grabowska, R., & Gear, A. R. (2002). Heat-shock protein 90 complexes in resting and thrombin-activated platelets. Biochemical and Biophysical Research Communications, 297, 129–133.PubMedCrossRefGoogle Scholar
  84. Suzuki, H., Kosuge, Y., Kobayashi, K., Kurosaki, Y., Ishii, N., Aoyama, N., Ishihara, K., & Ichikawa, T. (2017). Heat-shock protein 72 promotes platelet aggregation induced by various platelet activators in rats. Biomedical Research, 38, 175–182.PubMedCrossRefGoogle Scholar
  85. Swiatkowska, M., Padula, G., Michalec, L., Stasiak, M., Skurzynski, S., & Cierniewski, C. S. (2010). Ero1alpha is expressed on blood platelets in association with protein-disulfide isomerase and contributes to redox-controlled remodeling of alphaIIbbeta3. The Journal of Biological Chemistry, 285, 29874–29883.PubMedPubMedCentralCrossRefGoogle Scholar
  86. Theriault, J. R., Mambula, S. S., Sawamura, T., Stevenson, M. A., & Calderwood, S. K. (2005). Extracellular HSP70 binding to surface receptors present on antigen presenting cells and endothelial/epithelial cells. FEBS Letters, 579, 1951–1960.PubMedCrossRefGoogle Scholar
  87. Tokuda, H., Kuroyanagi, G., Tsujimoto, M., Enomoto, Y., Matsushima-Nishiwaki, R., Onuma, T., Kojima, A., Doi, T., Tanabe, K., Akamatsu, S., Iida, H., Ogura, S., Otsuka, T., Iwama, T., Tanikawa, T., Ishikawa, K., Kojima, K., & Kozawa, O. (2015). Release of phosphorylated HSP27 (HSPB1) from platelets is accompanied with the acceleration of aggregation in diabetic patients. PLoS One, 10, e0128977.PubMedPubMedCentralCrossRefGoogle Scholar
  88. Traister, A., Walsh, M., Aafaqi, S., Lu, M., Dai, X., Henkleman, M. R., Momen, A., Zhou, Y. Q., Husain, M., Arab, S., Piran, S., Hannigan, G., & Coles, J. G. (2013). Mutation in integrin-linked kinase (ILK(R211A)) and heat-shock protein 70 comprise a broadly cardioprotective complex. PLoS One, 8, e77331.PubMedPubMedCentralCrossRefGoogle Scholar
  89. Tran, H., Tanaka, A., Litvinovich, S. V., Medved, L. V., Haudenschild, C. C., & Argraves, W. S. (1995). The interaction of fibulin-1 with fibrinogen. A potential role in hemostasis and thrombosis. The Journal of Biological Chemistry, 270, 19458–19464.PubMedCrossRefGoogle Scholar
  90. Tucker, K. L., Sage, T., Stevens, J. M., Jordan, P. A., Jones, S., Barrett, N. E., St-Arnaud, R., Frampton, J., Dedhar, S., & Gibbins, J. M. (2008). A dual role for integrin-linked kinase in platelets: Regulating integrin function and alpha-granule secretion. Blood, 112, 4523–4531.PubMedPubMedCentralCrossRefGoogle Scholar
  91. Vega, V. L., Rodriguez-Silva, M., Frey, T., Gehrmann, M., Diaz, J. C., Steinem, C., Multhoff, G., Arispe, N., & De Maio, A. (2008). Hsp70 translocates into the plasma membrane after stress and is released into the extracellular environment in a membrane-associated form that activates macrophages. Journal of Immunology, 180, 4299–4307.CrossRefGoogle Scholar
  92. Verba, K. A., & Agard, D. A. (2017). How Hsp90 and Cdc37 lubricate kinase molecular switches. Trends in Biochemical Sciences, 42(10), 799–811.PubMedCrossRefGoogle Scholar
  93. Vinokurov, M., Ostrov, V., Yurinskaya, M., Garbuz, D., Murashev, A., Antonova, O., & Evgen'ev, M. (2012). Recombinant human Hsp70 protects against lipoteichoic acid-induced inflammation manifestations at the cellular and organismal levels. Cell Stress & Chaperones, 17, 89–101.CrossRefGoogle Scholar
  94. Wadhwa, R., Sugihara, T., Yoshida, A., Nomura, H., Reddel, R. R., Simpson, R., Maruta, H., & Kaul, S. C. (2000). Selective toxicity of MKT-077 to cancer cells is mediated by its binding to the hsp70 family protein mot-2 and reactivation of p53 function. Cancer Research, 60, 6818–6821.PubMedGoogle Scholar
  95. Wang, L., Wu, Y., Zhou, J., Ahmad, S. S., Mutus, B., Garbi, N., Hammerling, G., Liu, J., & Essex, D. W. (2013). Platelet-derived ERp57 mediates platelet incorporation into a growing thrombus by regulation of the alphaIIbbeta3 integrin. Blood, 122, 3642–3650.PubMedPubMedCentralCrossRefGoogle Scholar
  96. Wang, Y. L., Shen, H. H., Cheng, P. Y., Chu, Y. J., Hwang, H. R., Lam, K. K., & Lee, Y. M. (2016). 17-DMAG, an HSP90 inhibitor, ameliorates multiple organ dysfunction syndrome via induction of HSP70 in Endotoxemic rats. PLoS One, 11, e0155583.PubMedPubMedCentralCrossRefGoogle Scholar
  97. Watson, S. P. (2009). Platelet activation by extracellular matrix proteins in haemostasis and thrombosis. Current Pharmaceutical Design, 15, 1358–1372.PubMedCrossRefGoogle Scholar
  98. Watson, S. P., Auger, J. M., McCarty, O. J., & Pearce, A. C. (2005). GPVI and integrin alphaIIb beta3 signaling in platelets. Journal of Thrombosis and Haemostasis, 3, 1752–1762.PubMedCrossRefGoogle Scholar
  99. Williamson, D. S., Borgognoni, J., Clay, A., Daniels, Z., Dokurno, P., Drysdale, M. J., Foloppe, N., Francis, G. L., Graham, C. J., Howes, R., Macias, A. T., Murray, J. B., Parsons, R., Shaw, T., Surgenor, A. E., Terry, L., Wang, Y., Wood, M., & Massey, A. J. (2009). Novel adenosine-derived inhibitors of 70 kDa heat shock protein, discovered through structure-based design. Journal of Medicinal Chemistry, 52, 1510–1513.PubMedCrossRefGoogle Scholar
  100. Wonerow, P., Obergfell, A., Wilde, J. I., Bobe, R., Asazuma, N., Brdicka, T., Leo, A., Schraven, B., Horejsi, V., Shattil, S. J., & Watson, S. P. (2002). Differential role of glycolipid-enriched membrane domains in glycoprotein VI- and integrin-mediated phospholipase Cgamma2 regulation in platelets. The Biochemical Journal, 364, 755–765.PubMedPubMedCentralCrossRefGoogle Scholar
  101. Wyatt, A. R., Yerbury, J. J., Ecroyd, H., & Wilson, M. R. (2013). Extracellular chaperones and proteostasis. Annual Review of Biochemistry, 82, 295–322.PubMedCrossRefGoogle Scholar
  102. Zeiler, M., Moser, M., & Mann, M. (2014). Copy number analysis of the murine platelet proteome spanning the complete abundance range. Molecular & Cellular Proteomics, 13, 3435–3445.CrossRefGoogle Scholar
  103. Zhang, G., Liu, Z., Ding, H., Zhou, Y., Doan, H. A., Sin, K. W. T., Zhu, Z. J., Flores, R., Wen, Y., Gong, X., Liu, Q., & Li, Y. P. (2017). Tumor induces muscle wasting in mice through releasing extracellular Hsp70 and Hsp90. Nature Communications, 8, 589.PubMedPubMedCentralCrossRefGoogle Scholar
  104. Zhu, Y., O'Neill, S., Saklatvala, J., Tassi, L., & Mendelsohn, M. E. (1994). Phosphorylated HSP27 associates with the activation-dependent cytoskeleton in human platelets. Blood, 84, 3715–3723.PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Rachel A. Rigg
    • 1
  • Owen J. T. McCarty
    • 1
    • 2
    • 3
  • Joseph E. Aslan
    • 4
    • 5
  1. 1.Department of Biomedical EngineeringOregon Health & Science UniversityPortlandUSA
  2. 2.Department of Cell, Developmental & Cancer BiologyOregon Health & Science UniversityPortlandUSA
  3. 3.Division of Hematology and Medical OncologyOregon Health & Science UniversityPortlandUSA
  4. 4.Department of Biochemistry and Molecular BiologyOregon Health & Science UniversityPortlandUSA
  5. 5.Knight Cardiovascular Institute, School of MedicineOregon Health & Science UniversityPortlandUSA

Personalised recommendations