Deletion of a conserved juxtamembrane sequence in Trk abolishes NGF-promoted neuritogenesis.
Deletion of a conserved juxtamembrane sequence (KFG) in the Trk NGF receptor resulted in impaired neurite outgrowth, somatic hypertrophy, and induction of c-fos, c-jun, and TIS1 immediate-early genes. In contrast, these receptors retained the ability to mediate NGF-promoted survival and TIS8 and TIS11 immediate-early gene induction. The mutated receptor also mediated unimpaired autophosphorylation; SHC, PLC-gamma 1, and ERK tyrosine phosphorylation; and PI-3 kinase and ERK activation. However, SNT protein tyrosine phosphorylation, which wild-type receptors mediate via a ras-independent pathway, was undetectable. These findings indicate that the KFG sequence is indispensable for activating a ras-independent NGF signaling pathway involved in promoting neuronal differentiation and highlight potential roles of non-tyrosine-containing receptor domains in growth factor signal transduction.
Peng
X
X
Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Greene
L A
LA
Kaplan
D R
DR
Stephens
R M
RM
D019870:1-Phosphatidylinositol 4-Kinase; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000595:Amino Acid Sequence; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D048429:Cell Size; D016895:Culture Media, Serum-Free; D007527:Isoenzymes / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016501:Neurites / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D016716:PC12 Cells; D051966:Phospholipase C gamma; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D017384:Sequence Deletion; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D010738:Type C Phospholipases / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D016895:Culture Media, Serum-Free; D007527:Isoenzymes; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D017475:Receptors, Nerve Growth Factor; D055765:Shc Signaling Adaptor Proteins; C528035:Shc1 protein, rat; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D017853:Phosphotransferases (Alcohol Group Acceptor); D019870:1-Phosphatidylinositol 4-Kinase; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D010738:Type C Phospholipases; D051966:Phospholipase C gamma