Receptor binding specificities of Herstatin and its intron 8-encoded domain.
Retention of intron 8 in alternative HER-2 mRNA generates an inhibitory secreted ligand, Herstatin, with a novel receptor-binding domain (RBD) encoded by the intron. This study examines binding interactions with several receptors and investigates sequence variations in intron 8. The RBD, expressed as a peptide, binds at nM concentrations to HER-2, the EGFR, DeltaEGFR, HER-4 and to the IGF-1 receptor, but not to HER-3 nor to the FGF-3 receptor, whereas a rare mutation in the RBD (Arg to Ile) eliminates receptor binding. The full-length Herstatin binds with 3-4-fold higher affinity than its RBD, but with approximately 10-fold lower affinity to the IGF-IR. Sequence conservation in rhesus monkey but not in rat suggests that intron 8 recently diverged as a receptor-binding module critical for the function of Herstatin.
Shamieh
Lara S
LS
Oregon Health & Science University, Department of Biochemistry and Molecular Biology, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
Evans
Adam J
AJ
Denton
Michael C
MC
Clinton
Gail M
GM
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007438:Introns; D051379:Mice; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
D002352:Carrier Proteins; D017931:DNA Primers; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; C434665:herstatin; D020794:Receptor Protein-Tyrosine Kinases