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Signaling requirements for oncogenic forms of the Met tyrosine kinase receptor
M Jeffers1, S Koochekpour, M Fiscella
1ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Maryland 21702, USA.
Abstract:
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.
Insights
The Met receptor
Area of Science:
- Oncogenic signaling pathways
- Receptor tyrosine kinases
- Cancer biology
Background:
- The Met tyrosine kinase receptor plays a role in human cancers.
- Oncogenic Met signaling is crucial for cancer development.
- Previous research highlighted specific tyrosine residues and Grb2 binding sites for Met function.
Purpose of the Study:
- To investigate the signaling requirements of three oncogenic Met forms: wild type Met, mutationally activated Met, and Tpr-Met.
- To identify novel tyrosine residues critical for Met oncogene signaling.
- To differentiate the signaling strategies of various oncogenic Met forms.
Main Methods:
- Substitution of intracellular tyrosines with phenylalanine in oncogenic Met variants.
- Assessment of transforming activity, mitogenicity, and invasion in vitro.
- Evaluation of tumorigenicity and metastasis in vivo.
Main Results:
- Transforming activity of Met oncogenes depends on tyrosines Y8, Y9, Y14, Y15, and newly identified Y6 and Y10.
- Tyrosines Y6 and Y10 are critical for Met-mediated in vitro and in vivo responses.
- Tpr-Met exhibits a greater dependence on its Grb2 binding site compared to other oncogenic Met forms.
Conclusions:
- Met oncogenic signaling relies on specific tyrosine residues, including novel sites Y6 and Y10.
- Tyrosines Y6 and Y10 are essential for Met's oncogenic functions.
- Tpr-Met utilizes a distinct signaling strategy compared to other oncogenic Met variants.