Differential utilization of Trk autophosphorylation sites.
Tyrosine autophosphorylation controls the catalytic and signaling activities of the neurotrophin receptors, the Trks. To analyze the regulation of distinct tyrosine sites, we generated a panel of antibodies that report the phosphorylation state of individual tyrosines within the Trk cytoplasmic domain. Using pheochromocytoma-derived cell lines, we show that individual tyrosines within the nerve growth factor receptor TrkA are phosphorylated in a non-coordinate fashion following receptor activation. The non-coordinate response of these tyrosines reflects their separate functions in regulating the catalytic and signaling activities of Trk receptors. The differential utilization of distinct sites on Trk receptor tyrosine kinases suggests that the receptor can specify both the timing and the nature of neurotrophin-stimulated signal transduction pathways. Moreover, we show that these Trk autophosphorylation sites, which have hitherto been mapped and characterized only in non-neuronal cell lines, are activated in normal neurons in response to ligand stimulation.
Segal
R A
RA
Department of Neurology, Harvard Medical School and the Beth Israel Hospital, Boston, Massachusetts 02115, USA.
Bhattacharyya
A
A
Rua
L A
LA
Alberta
J A
JA
Stephens
R M
RM
Kaplan
D R
DR
Stiles
C D
CD
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D007158:Immunologic Techniques; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000494:pharmacology; D016716:PC12 Cells; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D020801:Receptor, Ciliary Neurotrophic Factor; D020917:Receptor, trkA; D020812:Receptor, trkC; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014638:Vanadates / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D009414:Nerve Growth Factors; D011506:Proteins; D011518:Proto-Oncogene Proteins; D020801:Receptor, Ciliary Neurotrophic Factor; D017475:Receptors, Nerve Growth Factor; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; C528035:Shc1 protein, rat; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D019000:Phosphotyrosine; D014638:Vanadates; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; D020812:Receptor, trkC; D010749:Phosphoprotein Phosphatases