Functional diversity of endothelin pathways in human lung fibroblasts may be based on structural diversity of the endothelin receptors.
Posttranslational modifications of the endothelin receptors A and B from human lung fibroblasts were investigated before and after stimulation of the cells with (dA)(30)-5'-S-EMC-endothelin-1. The patterns of phosphorylation and palmitoylation of both receptors were much more complicated than expected. In both the stimulated and the unstimulated states, multiple isoforms differing in the number and location of posttranslational modifications were present. MS analyses suggested rapid changes in these isoforms following stimulation. Overall, the ETA receptor was modified at 20 sites (15 phosphorylation, five palmitoylation sites) and ETB at 17 sites (13 phosphorylation, four palmitoylation sites). Part of the structural diversity involved hypermodification of short sequence regions, and it is suggested that this could represent a mechanism for incremental modulation of receptor activity. It is postulated that the observed structural diversity over disparate parts of the receptor sequences forms the basis for parallel stimulation of different signaling pathways at spatially and functionally distinct ET receptors differing in posttranslational modifications.
Stannard
Corinne
C
Centre for Molecular Medicine, Department of Medicine, University College, London, United Kingdom.
Lehenkari
Petri
P
Godovac-Zimmermann
Jasminka
J
D000595:Amino Acid Sequence; D002460:Cell Line; D019332:Endothelin-1 / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D005347:Fibroblasts / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008168:Lung / Q000737:chemistry / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D008969:Molecular Sequence Data; D011499:Protein Processing, Post-Translational; D044022:Receptor, Endothelin A / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D044023:Receptor, Endothelin B / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D021241:Spectrometry, Mass, Electrospray Ionization; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013329:Structure-Activity Relationship; D013388:Succinimides / Q000737:chemistry
D019332:Endothelin-1; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013388:Succinimides; C072682:N-(epsilon-maleimidocaproyloxy)succinimide