Identification of Shc docking site on Ret tyrosine kinase

Elena Arighi, Luisella Alberti, Francesca Torriti, Simona Ghizzoni, Maria Grazia Rizzetti, Giuliana Pelicci, Barbara Pasini, Italia Bongarzone, Claudia Piutti, Marco A. Pierotti, Maria Grazia Borrello

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Abstract

The RET proto-oncogene encodes two isoforms of a receptor type tyrosine kinase which plays a role in neural crest and kidney development. Distinct germ-line mutations of RET have been associated with the inherited cancer syndromes MEN2A, MEN2B and FMTC as well as with the congenital disorder Hirschsprung disease (HSCR), whereas somatic rearrangements (RET/PTCs) have been frequently detected in the papillary thyroid carcinoma. Despite these findings, suggesting a relevant role for RET product in development and neoplastic processes, little is known about the signalling triggered by this receptor. In this study, we have demonstrated that the transducing adaptor molecule Shc is recruited and activated by both Ret isoforms and by the rearranged cytoplasmatic Ret/ptc2 oncoproteins as well as by the membrane bound receptor activated by MEN2A or by MEN2B associated mutations. Moreover, our analysis has identified the Ret tyrosine residue and the Shc domains involved in the interaction. In fact, here we show that both the phosphotyrosine binding domains of Shc, PTB and SH2, interact with Ret/ptc2 in vitro, However, PTB domain binds 20 folds higher amount of Ret/ptc2 than SH2. The putative binding site for either SH2 and PTB domains has been identified as Tyr586 of Ret/ptc2, (Tyr1062 on proto-Ret). In keeping with this finding, by using RET/PTC2-Y586F mutant, we have demonstrated that this tyrosine residue, the last amino acid but one before the divergence of the two Ret isoforms, is the docking site for Shc.

Original languageEnglish
Pages (from-to)773-782
Number of pages10
JournalOncogene
Volume14
Issue number7
Publication statusPublished - 1997

Fingerprint

Protein-Tyrosine Kinases
Protein Isoforms
Tyrosine
Neoplastic Processes
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Hirschsprung Disease
Phosphotyrosine
Factor IX
src Homology Domains
Proto-Oncogenes
Germ-Line Mutation
Neural Crest
Oncogene Proteins
Receptor Protein-Tyrosine Kinases
Binding Sites
Kidney
Amino Acids
Mutation
Membranes
Neoplasms

Keywords

  • Oncogene
  • Receptor tyrosine kinase
  • Ret
  • Shc

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Arighi, E., Alberti, L., Torriti, F., Ghizzoni, S., Rizzetti, M. G., Pelicci, G., ... Borrello, M. G. (1997). Identification of Shc docking site on Ret tyrosine kinase. Oncogene, 14(7), 773-782.

Identification of Shc docking site on Ret tyrosine kinase. / Arighi, Elena; Alberti, Luisella; Torriti, Francesca; Ghizzoni, Simona; Rizzetti, Maria Grazia; Pelicci, Giuliana; Pasini, Barbara; Bongarzone, Italia; Piutti, Claudia; Pierotti, Marco A.; Borrello, Maria Grazia.

In: Oncogene, Vol. 14, No. 7, 1997, p. 773-782.

Research output: Contribution to journalArticle

Arighi, E, Alberti, L, Torriti, F, Ghizzoni, S, Rizzetti, MG, Pelicci, G, Pasini, B, Bongarzone, I, Piutti, C, Pierotti, MA & Borrello, MG 1997, 'Identification of Shc docking site on Ret tyrosine kinase', Oncogene, vol. 14, no. 7, pp. 773-782.
Arighi E, Alberti L, Torriti F, Ghizzoni S, Rizzetti MG, Pelicci G et al. Identification of Shc docking site on Ret tyrosine kinase. Oncogene. 1997;14(7):773-782.
Arighi, Elena ; Alberti, Luisella ; Torriti, Francesca ; Ghizzoni, Simona ; Rizzetti, Maria Grazia ; Pelicci, Giuliana ; Pasini, Barbara ; Bongarzone, Italia ; Piutti, Claudia ; Pierotti, Marco A. ; Borrello, Maria Grazia. / Identification of Shc docking site on Ret tyrosine kinase. In: Oncogene. 1997 ; Vol. 14, No. 7. pp. 773-782.
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AU - Arighi, Elena

AU - Alberti, Luisella

AU - Torriti, Francesca

AU - Ghizzoni, Simona

AU - Rizzetti, Maria Grazia

AU - Pelicci, Giuliana

AU - Pasini, Barbara

AU - Bongarzone, Italia

AU - Piutti, Claudia

AU - Pierotti, Marco A.

AU - Borrello, Maria Grazia

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AB - The RET proto-oncogene encodes two isoforms of a receptor type tyrosine kinase which plays a role in neural crest and kidney development. Distinct germ-line mutations of RET have been associated with the inherited cancer syndromes MEN2A, MEN2B and FMTC as well as with the congenital disorder Hirschsprung disease (HSCR), whereas somatic rearrangements (RET/PTCs) have been frequently detected in the papillary thyroid carcinoma. Despite these findings, suggesting a relevant role for RET product in development and neoplastic processes, little is known about the signalling triggered by this receptor. In this study, we have demonstrated that the transducing adaptor molecule Shc is recruited and activated by both Ret isoforms and by the rearranged cytoplasmatic Ret/ptc2 oncoproteins as well as by the membrane bound receptor activated by MEN2A or by MEN2B associated mutations. Moreover, our analysis has identified the Ret tyrosine residue and the Shc domains involved in the interaction. In fact, here we show that both the phosphotyrosine binding domains of Shc, PTB and SH2, interact with Ret/ptc2 in vitro, However, PTB domain binds 20 folds higher amount of Ret/ptc2 than SH2. The putative binding site for either SH2 and PTB domains has been identified as Tyr586 of Ret/ptc2, (Tyr1062 on proto-Ret). In keeping with this finding, by using RET/PTC2-Y586F mutant, we have demonstrated that this tyrosine residue, the last amino acid but one before the divergence of the two Ret isoforms, is the docking site for Shc.

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