A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family.
Signaling by tyrosine kinase receptors is mediated by selective interactions between individual Src homology 2 (SH2) domains of cytoplasmic effectors and specific phosphotyrosine residues in the activated receptor. Here, we report the existence in the hepatocyte growth factor/scatter factor (HGF/SF) receptor of a multifunctional docking site made of the tandemly arranged degenerate sequence YVH/NV. Phosphorylation of this site mediates intermediate- to high-affinity interactions with multiple SH2-containing signal transducers, including phosphatidylinositol 3-kinase, phospholipase C gamma, pp60c-src, and the GRB-2-Sos complex. Mutation of the two tyrosines results in loss of biological function, as shown by abrogation of the transforming activity in the oncogenic counterpart of the receptor. The same bidentate motif is conserved in the evolutionarily related receptors Sea and Ron, suggesting that in all members of the HGF/SF receptor family, signal transduction is channeled through a multifunctional binding site.
Ponzetto
C
C
Department of Biomedical Sciences and Oncology, University of Torino Medical School, Italy.
Bardelli
A
A
Zhen
Z
Z
Maina
F
F
dalla Zonca
P
P
Giordano
S
S
Graziani
A
A
Panayotou
G
G
Comoglio
P M
PM
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D051380:GRB2 Adaptor Protein; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D028861:Nuclear Pore Complex Proteins; D019869:Phosphatidylinositol 3-Kinases; D010748:Phosphopeptides / Q000138:chemical synthesis / Q000378:metabolism; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000032:analysis; D011505:Protein-Tyrosine Kinases / Q000032:analysis; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D020664:Son of Sevenless Proteins; D010738:Type C Phospholipases / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; D017228:Hepatocyte Growth Factor; D008565:Membrane Proteins; D019950:Mitogen-Activated Protein Kinase 1; D028861:Nuclear Pore Complex Proteins; D019869:Phosphatidylinositol 3-Kinases; D010748:Phosphopeptides; D017853:Phosphotransferases (Alcohol Group Acceptor); D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019859:Proto-Oncogene Proteins c-met; D016392:Proto-Oncogene Proteins pp60(c-src); D020794:Receptor Protein-Tyrosine Kinases; D020664:Son of Sevenless Proteins; D010738:Type C Phospholipases; C073597:TPR protein, human