Activating mutations in the Met receptor overcome the requirement for autophosphorylation of tyrosines crucial for wild type signaling.
Mutations in Met have been identified in human cancer, and we have previously shown that these mutations deregulate the enzymatic activity of this tyrosine kinase receptor, thereby unleashing its oncogenic potential. Signal transduction via wild type Met has been shown to require the autophosphorylation of two tyrosine doublets; Y8,9 which functions to enhance enzymatic activity, and Y14,15 which provides docking sites for signaling molecules, and in the present investigation we examine the importance of these residues for signaling via mutationally activated Met. We find that activating mutations introduced into a membrane-spanning Met receptor circumvent the normally stringent requirement for Y8,9 phosphorylation, and do so in a largely ligand-dependent fashion. Similarly, activating mutations introduced into a constitutively dimerized cytoplasmic form of Met (i.e. Tpr-Met) facilitate its autophosphorylation and oncogenic activity in the absence of Y8,9 phosphorylation. We also find that activating mutations allow a membrane-spanning Met receptor to overcome the requirement for the Y14,15 phosphorylation in a manner which is largely ligand-independent. These findings support a model whereby activating mutations stabilize an active conformation of the Met kinase via a mechanism which can function independently of Y8,9 autophosphorylation and suggest that signaling via wild type Met and mutationally activated Met may proceed through distinct pathways.
Jeffers
M F
MF
ABL-Basic Research Program, NCI-FCRDC, Frederick, Maryland, MD 21702, USA.
Vande Woude
G F
GF
D016475:3T3 Cells; D000818:Animals; D006801:Humans; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D020800:Receptor, Nerve Growth Factor / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism*
D020800:Receptor, Nerve Growth Factor; D011993:Recombinant Fusion Proteins; D014443:Tyrosine; D019859:Proto-Oncogene Proteins c-met