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.
journal_name
Oncogenejournal_title
Oncogeneauthors
Hallberg B,Ashcroft M,Loeb DM,Kaplan DR,Downward Jdoi
10.1038/sj.onc.1201980subject
Has Abstractpub_date
1998-08-13 00:00:00pages
691-7issue
6eissn
0950-9232issn
1476-5594journal_volume
17pub_type
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