Differential activation of formyl peptide receptor-like 1 by peptide ligands.
Formyl peptide receptor-like 1 (FPRL1) plays a key role in the regulation of immune responses. The activation of FPRL1 induces a complicated pattern of cellular signaling, which results in the regulation of several immune responses, such as chemotactic migration and the production of reactive oxygen species (ROS). Because some of these cellular responses are not beneficial to the host, ligands that selectively modulate these cellular responses are useful. His-Phe-Tyr-Leu-Pro-Met (HFYLPM) is a synthetic peptide that binds to FPRL1. In this study, we generated various HFYLPM analogues and examined their effects on cellular responses via FPRL1 in FPRL1-expressing rat basophilic leukemia-2H3 cells or in primary human neutrophils. Among the HXYLPM analogues, His-Arg-Tyr-Leu-Pro-Met (HRYLPM) activated a broad spectrum of cellular signaling events, including an intracellular Ca(2+) concentration increase, phosphoinositide 3-kinase, extracellular signal-regulated kinase, and Akt activation, however, His-Glu-Tyr-Leu-Pro-Met (HEYLPM) activated only intracellular Ca(2+) concentration and Akt but did not increase Ca(2+). In addition, HRYLPM was found to stimulate chemotaxis and ROS generation via phosphoinositide 3-kinase and an intracellular Ca(2+) concentration increase, respectively, whereas HEYLPM stimulated chemotaxis but not ROS generation. With respect to the molecular mechanisms involved in the differential action of HRYLPM and HEYLPM, we found that HRYLPM but not HEYLPM competitively inhibited the binding of (125)I-labeled Trp-Lys-Tyr-Met-Val-D-Met-NH(2) (WKYMVm, a FPRL1 ligand) to FPRL1. This study demonstrates that the important chemoattractant receptor, FPRL1, may be differentially modulated by distinct peptide ligands. We also suggest that HRYLPM and HEYLPM may be used to selectively modulate FPRL1.
Bae
Yoe-Sik
YS
Medical Research Center for Cancer Molecular Therapy and Department of Biochemistry, College of Medicine, Dong-A University, Seo-Gu, Busan, Korea. yoesik@donga.ac.kr
Yi
Hee Jeong
HJ
Lee
Ha-Young
HY
Jo
Eun Jin
EJ
Kim
Jung Im
JI
Lee
Taehoon G
TG
Ye
Richard D
RD
Kwak
Jong-Young
JY
Ryu
Sung Ho
SH
D000818:Animals; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002630:Chemotactic Factors / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism / Q000502:physiology; D007457:Iodine Radioisotopes / Q000378:metabolism; D008024:Ligands; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism / Q000502:physiology; D009842:Oligopeptides / Q000819:agonists / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology*; D010766:Phosphorylation; D011485:Protein Binding / Q000502:physiology; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D044042:Receptors, Formyl Peptide / Q000819:agonists / Q000096:biosynthesis / Q000378:metabolism*; D044067:Receptors, Lipoxin / Q000819:agonists / Q000096:biosynthesis / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013481:Superoxides / Q000378:metabolism
D002630:Chemotactic Factors; C105101:FPR2 protein, human; C465639:His-Phe-Tyr-Leu-Pro-Met; D007457:Iodine Radioisotopes; D008024:Ligands; D009842:Oligopeptides; D011518:Proto-Oncogene Proteins; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; C113617:Trp-Lys-Tyr-Met-Val-Met; D013481:Superoxides; D011505:Protein-Tyrosine Kinases; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium