Nerve growth factor induced stimulation of Ras requires Trk interaction with Shc but does not involve phosphoinositide 3-OH kinase

Bengt Hallberg, Margaret Ashcroft, David M. Loeb, David R. Kaplan, Julian Downward

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

The TrkA receptor protein tyrosine kinase is involved in signalling PC12 cell differentiation and cessation of cell division in response to nerve growth factor (NGF). To assess the importance of adaptor proteins and Ras in NGF control of phosphoinositide 3-OH kinase (PI 3-kinase), specific receptor mutations in Trk have been employed. We show that phosphorylation of tyrosine 490, but not 785, of Trk is essential for activation of both Ras and PI 3-kinase in vivo, correlating with tyrosine phosphorylation of Shc and binding of Shc to the adaptor Grb2 and the Ras exchange factor Sos. A mutant receptor that lacks Y490 and Y785, but contains an introduced YxxM motif which binds the regulatory domain of PI 3-kinase, is unable to activate Ras despite causing increased PI 3-kinase activity. This indicates clearly that activation of PI 3-kinase by itself is not sufficient to cause activation of Ras, arguing against a model in which PI 3-kinase acts upstream of Ras. The Shc site of Trk is thus crucial for the activation of Ras and PI 3-kinase.

Original languageEnglish (US)
Pages (from-to)691-697
Number of pages7
JournalOncogene
Volume17
Issue number6
StatePublished - Aug 13 1998
Externally publishedYes

Fingerprint

Nerve Growth Factor
Phosphatidylinositols
Phosphotransferases
Tyrosine
trkA Receptor
Phosphorylation
ras Proteins
PC12 Cells
Receptor Protein-Tyrosine Kinases
Cell Division
Cell Differentiation
Mutation

Keywords

  • Apoptosis
  • NGF
  • Phosphatidylinositol 3-kinase
  • PKB
  • Ras
  • Trk

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Nerve growth factor induced stimulation of Ras requires Trk interaction with Shc but does not involve phosphoinositide 3-OH kinase. / Hallberg, Bengt; Ashcroft, Margaret; Loeb, David M.; Kaplan, David R.; Downward, Julian.

In: Oncogene, Vol. 17, No. 6, 13.08.1998, p. 691-697.

Research output: Contribution to journalArticle

Hallberg, Bengt ; Ashcroft, Margaret ; Loeb, David M. ; Kaplan, David R. ; Downward, Julian. / Nerve growth factor induced stimulation of Ras requires Trk interaction with Shc but does not involve phosphoinositide 3-OH kinase. In: Oncogene. 1998 ; Vol. 17, No. 6. pp. 691-697.
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