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Fig. 2. Proposed signaling mechanisms of neutrophilic functions induced by mitocryptides.To identify receptor molecules for the mitocryptides, we crosslinked these peptides withintact neutrophilic-differentiated HL-60 cells, and found that MCT-1 was bound tomolecular complexes which consisted of at least five different proteins. Moreover, thereceptor molecule for MCT-2 in neutrophilic-differentiated HL-60 cells was shown to beformyl-peptide receptor like-1 (FPRL1) because the attenuation of FPRL1 expression by itssiRNA largely attenuated MCT-2-induced -hexosaminidase ( -HA) release from the cells.We also investigated their intracellular signaling mechanisms, and demonstrated that theneutrophilic function of -HA release was induced by G i - or G o -protein-dependentintracellular signaling events including [Ca 2+ ] i increase and ERK1/2 phosphorylation(Figure 2). We are now investigating each protein that forms receptor-protein complexesfor MCT-1. We are also comprehensively identifying many cryptides by bioinformaticapproach.AcknowledgmentsThe present study was supported by research grants from the Ministry of Education, Culture, Sports,Science and Technology, Japan (No. 21603014; 40089107) and a supplementary research aid fromNippon Boehringer Ingelheim Co., Ltd.References1. Mukai, H., Hokari, Y., Seki, T., Nakano, H., Takao, T., Shimonishi, Y., Nishi, Y., Munekata, E. InLebl, M., Houghten, R.A. (Eds.) Peptides: The Wave of the Future (Proceedings of the SecondInternational and the Seventeenth American Peptide Symposium), American Peptide Society, SanDiego, 2001, pp 1014-1015.2. Mukai, H., Matsuo, Y., Kamijo, R., Wakamatsu, K. In Chorev, M., Sawyer, T.K. (Eds.) PeptideRevolution: Genomics, Proteomics & Therapeutics (Proceedings of the Eighteenth AmericanPeptide Symposium), American Peptide Society, San Diego, 2004, pp 553-p555.3. Mukai, H., Hokari, Y., Seki, T., Takao, T., Kubota, M., Matsuo, Y., Tsukagoshi, H., Kato, M.,Kimura, H., Shimonishi, Y., Kiso, Y., Nishi, Y., Wakamatsu, K., Munekata, E. J. Biol. Chem. 283,30596-30605 (2008).4. Mukai, H., Seki, T., Nakano, H., Hokari, Y., Takao, T., Kawanami, M., Kiso, Y., Shimonishi, Y.,Nishi, Y., Munekata, E. J. Immunol. 182, 5072-5080 (2009).5. Ueki, N., Someya, K., Matsuo, Y., Wakamatsu, K., Mukai, H. Biopolymers (Pept. Sci.) 88, 190-198(2007).6. Ivanov, V.T., Karelin, A.A., Philippova, M.M., Nazimov I.V., Pletnev, V.Z. Biopolymers (Pept.Sci.) 43, 171-188 (1997).7. Gomes, I., Grushko, J.S., Golebiewska, U., Hoogendoorn, S., Gupta, A., Heimann, A.S., Ferro, E.S.,Scarlata, S., Fricker, L.D., Devi, L.A. FASEB J. 23, 3020-3029 (2009).37