RON is a heterodimeric tyrosine kinase receptor activated by the HGF homologue MSP.
RON, a cDNA homologous to the hepatocyte growth factor (HGF) receptor gene (MET), encodes a putative tyrosine kinase. Here we show that the RON gene is expressed in several epithelial tissues as well as in granulocytes and monocytes. The major RON transcript is translated into a glycosylated single chain precursor, cleaved into a 185 kDa heterodimer (p185RON) of 35 (alpha) and 150 kDa (beta) disulfide-linked chains, before exposure at the cell surface. The Ron beta-chain displays intrinsic tyrosine kinase activity in vitro, after immunoprecipitation by specific antibodies. In vivo, tyrosine phosphorylation of p185RON is induced by stimulation with macrophage stimulating protein (MSP), a protease-like factor containing four 'kringle' domains, homologous to HGF. In epithelial cells, MSP-induced tyrosine phosphorylation of p185RON is followed by DNA synthesis. p185RON is not activated by HGF, nor is the HGF receptor activated by MSP in biochemical and biological assays. p185RON is also activated by a pure recombinant protein containing only the N-terminal two kringles of MSP. These data show that p185RON is a tyrosine kinase activated by MSP and that it is member of a family of growth factor receptors with distinct specificities for structurally related ligands.
Gaudino
G
G
Department of Biomedical Sciences and Oncology, University of Torino Medical School, Italy.
Follenzi
A
A
Naldini
L
L
Collesi
C
C
Santoro
M
M
Gallo
K A
KA
Godowski
P J
PJ
Comoglio
P M
PM
D001483:Base Sequence; D002465:Cell Movement / Q000187:drug effects; D003001:Cloning, Molecular; D004261:DNA Replication / Q000187:drug effects; D004847:Epithelial Cells; D006133:Growth Substances / Q000235:genetics / Q000494:pharmacology*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D018082:Kringles; D008969:Molecular Sequence Data; D009928:Organ Specificity; D010766:Phosphorylation / Q000187:drug effects; D011487:Protein Conformation; D011498:Protein Precursors / Q000096:biosynthesis; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000032:analysis; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000302:isolation & purification; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
D006133:Growth Substances; D011498:Protein Precursors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; C082332:macrophage stimulating protein; D014443:Tyrosine; D017228:Hepatocyte Growth Factor; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases