Use of signal specific receptor tyrosine kinase oncoproteins reveals that pathways downstream from Grb2 or Shc are sufficient for cell ... View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2002-03-13

AUTHORS

Caroline Saucier, Vasilios Papavasiliou, Alexander Palazzo, Monica A Naujokas, Richard Kremer, Morag Park

ABSTRACT

Many human cancers have been associated with the deregulation of receptor tyrosine kinases (RTK). However, the individual contribution of receptor-associated signaling proteins in cellular transformation and metastasis is poorly understood. To examine the role of RTK activated signal transduction pathways to processes involved in cell transformation, we have exploited the oncogenic derivative of the Met RTK (Tpr–Met). Unlike other RTKs, twin tyrosine residues in the carboxy-terminal tail of the Met oncoprotein and receptor are required for all biological and transforming activities, and a mutant lacking these tyrosines is catalytically active but non transforming. Using this mutant we have inserted oligonucleotide cassettes, each encoding a binding site for a specific signaling protein derived from other RTKs. We have generated variant forms of the Tpr–Met oncoprotein with the ability to bind individually to the p85 subunit of PI3′K, PLCγ, or to the Grb2 or Shc adaptor proteins. Variants that recruit the Shc or Grb2 adaptor proteins generated foci of morphologically transformed fibroblast cells and induced anchorage-independent growth, scattering of epithelial cells and experimental metastasis. In contrast, variants that bind and activate PI3′K or PLCγ failed to generate readily detectable foci. Although cell lines expressing the PI3′K variant grew in soft-agar, these cells were non metastatic. Using this unique RTK oncoprotein model, we have established that Grb2 or Shc dependent signaling pathways are sufficient for cell transformation and metastatic spread. More... »

PAGES

1800-1811

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/sj.onc.1205261

DOI

http://dx.doi.org/10.1038/sj.onc.1205261

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1031681974

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/11896612


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48 schema:description Many human cancers have been associated with the deregulation of receptor tyrosine kinases (RTK). However, the individual contribution of receptor-associated signaling proteins in cellular transformation and metastasis is poorly understood. To examine the role of RTK activated signal transduction pathways to processes involved in cell transformation, we have exploited the oncogenic derivative of the Met RTK (Tpr–Met). Unlike other RTKs, twin tyrosine residues in the carboxy-terminal tail of the Met oncoprotein and receptor are required for all biological and transforming activities, and a mutant lacking these tyrosines is catalytically active but non transforming. Using this mutant we have inserted oligonucleotide cassettes, each encoding a binding site for a specific signaling protein derived from other RTKs. We have generated variant forms of the Tpr–Met oncoprotein with the ability to bind individually to the p85 subunit of PI3′K, PLCγ, or to the Grb2 or Shc adaptor proteins. Variants that recruit the Shc or Grb2 adaptor proteins generated foci of morphologically transformed fibroblast cells and induced anchorage-independent growth, scattering of epithelial cells and experimental metastasis. In contrast, variants that bind and activate PI3′K or PLCγ failed to generate readily detectable foci. Although cell lines expressing the PI3′K variant grew in soft-agar, these cells were non metastatic. Using this unique RTK oncoprotein model, we have established that Grb2 or Shc dependent signaling pathways are sufficient for cell transformation and metastatic spread.
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57 MET oncoprotein
58 Met receptor tyrosine kinase
59 PI3′K
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65 Tpr-Met oncoprotein
66 ability
67 activity
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69 anchorage-independent growth
70 binds
71 cancer
72 carboxy-terminal tail
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74 cell lines
75 cell transformation
76 cells
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78 contrast
79 contribution
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81 derivatives
82 detectable foci
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85 fibroblast cells
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88 growth
89 human cancers
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