Signaling requirements for oncogenic forms of the Met tyrosine kinase receptor.
The Met tyrosine kinase receptor has been implicated in human cancer. Here we have examined the signaling requirements of three oncogenic forms of this molecule: wild type Met in response to ligand/autocrine stimulation, Met which has been mutationally activated, and Tpr-Met (a constitutively active truncated Met fusion protein). Previous studies have demonstrated the importance of a Grb2 binding site, and of specific tyrosine residues (i.e. Y8,9 and Y14,15) for Met function, and we have now explored the relevance of these and other sites for oncogenic Met signaling. Following substitution of various intracellular tyrosines for phenylalanine, we find that the transforming activity of each Met oncogene is dependent upon tyrosines Y8,9 and Y14,15, in addition to two novel tyrosines (Y6 and Y10) not previously implicated in Met signaling. Tyrosines Y6 and Y10 influence a variety of Met-mediated responses both in vitro (transformation, mitogenicity and invasion), and in vivo (tumorigenicity and metastasis). We also show that Tpr-Met is much more dependent on its Grb2 binding site for biological activity than are the other oncogenic forms of the Met receptor. Thus, although the three Met oncogenes examined are similar in their dependency on a number of specific tyrosines for activity, the signaling strategy employed by Tpr-Met can be differentiated from that of the other two.
Jeffers
M
M
ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Maryland 21702, USA.
Koochekpour
S
S
Fiscella
M
M
Sathyanarayana
B K
BK
Vande Woude
G F
GF
D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D005260:Female; D051380:GRB2 Adaptor Protein; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009362:Neoplasm Metastasis; D009857:Oncogenes; D010649:Phenylalanine / Q000737:chemistry; D017354:Point Mutation; D011506:Proteins / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D017384:Sequence Deletion; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000737:chemistry
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; D011506:Proteins; D011993:Recombinant Fusion Proteins; D014443:Tyrosine; D010649:Phenylalanine; D019859:Proto-Oncogene Proteins c-met