Amyloid precursor-like protein 2 association with HLA class I molecules
- 157 Downloads
Amyloid precursor-like protein 2 (APLP2) is a ubiquitously expressed protein. The previously demonstrated functions for APLP2 include binding to the mouse major histocompatibility complex (MHC) class I molecule H-2Kd and down regulating its cell surface expression. In this study, we have investigated the interaction of APLP2 with the human leukocyte antigen (HLA) class I molecule in human tumor cell lines. APLP2 was readily detected in pancreatic, breast, and prostate tumor lines, although it was found only in very low amounts in lymphoma cell lines. In a pancreatic tumor cell line, HLA class I was extensively co-localized with APLP2 in vesicular compartments following endocytosis of HLA class I molecules. In pancreatic, breast, and prostate tumor lines, APLP2 was bound to the HLA class I molecule. APLP2 was found to bind to HLA-A24, and more strongly to HLA-A2. Increased expression of APLP2 resulted in reduced surface expression of HLA-A2 and HLA-A24. Overall, these studies demonstrate that APLP2 binds to the HLA class I molecule, co-localizes with it in intracellular vesicles, and reduces the level of HLA class I molecule cell surface expression.
KeywordsAmyloid precursor-like protein 2 Antigen presentation Human leukocyte antigen Major histocompatibility complex class I Tumor
We thank Dr. Shantaram Joshi, Dr. Kenneth Cowan, Dr. Vinod Labhasetwar, Dr. Michael A. Hollingsworth, Dr. Richard MacDonald, Dr. John Chan, Vivek Gautam, Christopher Connelly, Michelle Hartman, Himabindu Ramachandrareddy, Jaspreet Vasir, Tom Caffrey, Dr. Pankaj Singh, Dr. Wendy Maury, and Dr. Ted Hansen for their assistance with obtaining cell lines and antibodies, and we thank Dr. Atsunori Hiasa and Dr. Hiroshi Shiku for the HLA-A*2404 cDNA. We gratefully acknowledge the assistance of the personnel of the UNMC Cell Analysis Facility and the Monoclonal Antibody Facility. Core facilities at UNMC receive support from the NIH Cancer Center Support Grant P30CA036727. This work was supported by NIH Grants GM57428 (to J.C.S.) and GM74876 (to S.C.), an Eppley Cancer Center Pediatric Cancer Research Grant, UNMC Graduate Studies Fellowships (to A.T., M.S., and L.S.), a Nebraska Center for Cellular Signaling Fellowship and an American Heart Association Predoctoral Fellowship (to M.S.), an NIH Training Grant T32 CA009476 Fellowship (to L.S.), and a Graduate Assistance in Areas of National Need Fellowship (to H.C.).
- 9.Cerutti A, Zan H, Schaffer A, Bergsagel L, Harindranath N, Max EE, Casali P (1998) CD40 ligand and appropriate cytokines induce switching to IgG, IgA, and IgE and coordinated germinal center and plasmacytoid phenotypic differentiation in a human monoclonal IgM + IgD + B cell line. J Immunol 160:2145–2157PubMedGoogle Scholar
- 10.Covell DG, Wallqvist A, Rabow AA, Thanki N (2003) Molecular classification of cancer: unsupervised self-organizing map analysis of gene expression microarray data. Mol Cancer Therap 2:317–332Google Scholar
- 23.Miyahara Y, Naota H, Wang L, Hiasa A, Goto M, Watanabe M, Kitano S, Okumura S, Takemitsu T, Yuta A, Majima Y, Lemonnier FA, Boon T, Shiku H (2005) Determination of cellularly processed HLA-A2402-restricted novel CTL epitopes derived from two cancer germ line genes, MAGE-A4 and SAGE. Clin Cancer Res 11:5581–5589PubMedCrossRefGoogle Scholar
- 24.Morris CR, Petersen JL, Vargas SE, Turnquist HR, McIlhaney MM, Sanderson SD, Bruder JT, Yu YYL, Burgert H-G, Solheim JC (2003) The amyloid precursor-like protein 2 and the adenoviral E3/19K protein both bind to a conformational site on H-2Kd and regulate H-2Kd expression. J Biol Chem 278:12618–12623PubMedCrossRefGoogle Scholar
- 25.Mu FT, Callaghan JM, Steele-Mortimer O, Stenmark H, Parton RG, Campbell PL, McCluskey J, Yeo JP, Tock EP, Toh BH (1995) EEA1, an early endosome-associated protein: EEA1 is a conserved alpha-helical peripheral membrane protein flanked by cysteine “finger” and contains a calmodulin-binding IQ motif. J Biol Chem 270:133503–133511Google Scholar
- 30.Parham P, Brodsky FM (1981) Partial purification and some properties of BB7.2: a cytotoxic monoclonal antibody with specificity for HLA-A2 and a variant of HLA-A28Google Scholar
- 34.Ren M, Xu G, Zeng J, De Lemos-Chiarandini C, Adesnik M, Sabatini DD (1998) Hydrolysis of GTP on rab11 is required for the direct delivery of transferrin from the pericentriolar recycling compartment to the cell surface but not from sorting endosomes. Proc Natl Acad Sci USA 95:6187–6192PubMedCrossRefGoogle Scholar
- 40.Sharma M, Naslavsky N, Caplan S (2008) A role for EHD4 in the regulation of early endosomal transport. Traffic, epubGoogle Scholar
- 46.Stam NJ, Vroom TM, Peters PJ, Pastoors EB, Ploegh HL (1990) HLA-A- and HLA-B-specific monoclonal antibodies reactive with free heavy chains in western blots, in formalin-fixed, paraffin-embedded tissue sections and in cryo-immuno-electron microscopy. Int Immunol 2:113–125PubMedCrossRefGoogle Scholar
- 54.Walsh DM, Fadeeva JV, Lavoie MJ, Paliga K, Egger S, Kimberly WT, Wasco W, Selkoe DJ (2003) Gamma-secretase cleavage and binding to FE65 regulate the nuclear translocation of the intracellular C-terminal domain (ICD) of the APP family of proteins. Biochemistry 42:6664–6673PubMedCrossRefGoogle Scholar
- 55.Walsh DM, Minogue AM, Frigerio CS, Fadeeva JV, Wasco W, Selkoe DJ (2007) The APP family of proteins: similarities and differences. Biochem Soc Trans 5:416–420Google Scholar