| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Molecular and Cellular Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; and
Laboratory of Cellular Biochemistry, RIKEN (The Institute of Physical and Chemical Research), Saitama, Japan
Extracellular heat shock protein 70 (Hsp70) exerts profound effects both in mediating tumor rejection by Hsp70-based vaccines and in autoimmunity. Further progress in this area, however, awaits the identification of the cell surface receptors for extracellular Hsp70 that mediate its immune functions. We have examined a wide range of candidate Hsp70 receptors and find significant binding through two main families of cell surface proteins, including 1) the scavenger receptor (SR) family and 2) C-type lectins of the NK family. In addition, given that the anticancer effects of Hsp70 vaccines have been shown to involve uptake of Ags by APC exposed to Hsp70-tumor Ag complexes, we have examined the ability of the receptors identified here to internalize Hsp70-peptide complexes. Our findings indicate that three members of the SR family (lectin-like oxidized low density lipoprotein receptor 1; fasciclin, epidermal growth factor-like, laminin-type epidermal growth factor-like, and link domain-containing scavenger receptor-1; and SR expressed by endothelial cells-1) are able to bind Hsp70-peptide complexes and mediate its efficient internalization. Indeed, each of the SR was able to mediate efficient uptake of Hsp70 when transfected into Chinese hamster ovary cells previously null for uptake. Curiously, Hsp70 internalization occurs independently of the intracellular domains of the SR, and Hsp70 uptake could be detected when the entire intracellular domain of lectin-like oxidized low density lipoprotein receptor 1 or SR expressed by endothelial cells-1 was truncated. The existence of a wide repertoire of cell surface Hsp70-binding structures may permit intracellular responses to extracellular Hsp70 that are cell specific and discriminate between Hsp70 family members.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Research Grants R01CA047407 and RO1CA094397.
2 Address correspondence and reprint requests to Dr. Stuart K. Calderwood, Molecular and Cellular Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, 21-27 Burlington Avenue, Boston, MA 02215. E-mail address: scalderw{at}bidmc.harvard.edu
3 Abbreviations used in this paper: Hsp, heat shock protein; Hsp70.PC, Hsp70-peptide complex; LDL, low-density lipoprotein; oxLDL, oxidized LDL; acLDL, acetylated LDL; LRP1, LDL receptor-related protein-1; SR, scavenger receptor; LOX-1, lectin-like oxidized low-density lipoprotein receptor 1; FEEL-1, fasciclin, epidermal growth factor-like, laminin-type epidermal growth factor-like, and link domain-containing SR-1; SREC-1, SR expressed by endothelial cells-1; SR-PSOX, SR that binds phosphatidylserine and oxidized lipoprotein; CHO, Chinese hamster ovary; ID, intracellular domain. Grp94, glucose-regulated protein 94; NKG2D, killer cell lectin-like receptor subfamily K, member 1.
This article has been cited by other articles:
|
|
 |
|
  V. L. Vega, M. Rodriguez-Silva, T. Frey, M. Gehrmann, J. C. Diaz, C. Steinem, G. Multhoff, N. Arispe, and A. De Maio Hsp70 Translocates into the Plasma Membrane after Stress and Is Released into the Extracellular Environment in a Membrane-Associated Form that Activates Macrophages J. Immunol., March 15, 2008; 180(6): 4299 - 4307. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Srivastava, C. Varalakshmi, and A. Khar The Ischemia-Responsive Protein 94 (Irp94) Activates Dendritic Cells through NK Cell Receptor Protein-2/NK Group 2 Member D (NKR-P2/NKG2D) Leading to Their Maturation J. Immunol., January 15, 2008; 180(2): 1117 - 1130. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Kottke, L. Sanchez-Perez, R. M. Diaz, J. Thompson, H. Chong, K. Harrington, S. K. Calderwood, J. Pulido, N. Georgopoulos, P. Selby, et al. Induction of hsp70-Mediated Th17 Autoimmunity Can Be Exploited as Immunotherapy for Metastatic Prostate Cancer Cancer Res., December 15, 2007; 67(24): 11970 - 11979. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Kettner, F. Kalthoff, P. Graf, E. Priller, F. Kricek, I. Lindley, and T. Schweighoffer EWI-2/CD316 Is an Inducible Receptor of HSPA8 on Human Dendritic Cells Mol. Cell. Biol., November 1, 2007; 27(21): 7718 - 7726. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. SHERMAN and G. MULTHOFF Heat Shock Proteins in Cancer Ann. N.Y. Acad. Sci., October 1, 2007; 1113(1): 192 - 201. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. K. CALDERWOOD, S. S. MAMBULA, and P. J. GRAY JR Extracellular Heat Shock Proteins in Cell Signaling and Immunity Ann. N.Y. Acad. Sci., October 1, 2007; 1113(1): 28 - 39. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
