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Beta PDGF receptor mutants defective for mitogenesis promote neurite outgrowth in PC12 cells.

AbstractBACKGROUND:
Platelet-derived growth factor (PDGF) promotes mitogenesis in fibroblast cell lines but stimulates neurite outgrowth in PC12 cells that ectopically express the beta PDGF receptor. To determine which substrates must associate with this receptor protein-tyrosine kinase in order to promote neurite outgrowth, we introduced into PC12 pheochromocytoma cells three mutant forms of the beta PDGF receptor that no longer associate with specific substrate proteins. We then assayed the ability of these receptor mutants to affect neurite extension.
RESULTS:
Receptors lacking the kinase-insert domain did not associate with either phosphatidylinositol 3-kinase (PI 3-kinase) or Ras GTPase-activating protein (Ras-GAP) in PC12 cells. A carboxy-terminal truncation of the beta PDGF receptor eliminated the association of phospholipase C-gamma 1 (PLC-gamma 1) with the receptor and prevented phosphorylation of PLC-gamma 1 in PC12 cells. Finally, beta PDGF receptors that have tyrosine-to-phenylalanine point mutations at positions 708, 719, 977 and 989 did not associate with either PI 3-kinase or PLC-gamma 1. All three mutant forms of the beta PDGF receptor promoted PDGF-dependent neurite outgrowth in PC12 cells and elicited activation of mitogen-activated protein (MAP) kinases.
CONCLUSIONS:
PC12 cells expressing the beta PDGF receptor extend neurites in response to PDGF in the absence of signalling through PI 3-kinase, RasGAP, and PLC-gamma 1. This contrasts with the requirements for mitogenesis for epithelial and fibroblast cell lines, in which the association of PI 3-kinase with the beta PDGF receptor is essential. This receptor protein-tyrosine kinase therefore phosphorylates and activates a similar set of intracellular signalling molecules in the context of both mitogenesis and differentiation, but the importance of particular pathways for each phenotypic response is distinct.
AuthorsM L Vetter, J M Bishop
JournalCurrent biology : CB (Curr Biol) Vol. 5 Issue 2 Pg. 168-78 (Feb 01 1995) ISSN: 0960-9822 [Print] England
PMID7743180 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • GTPase-Activating Proteins
  • Intracellular Signaling Peptides and Proteins
  • Isoenzymes
  • Platelet-Derived Growth Factor
  • Proteins
  • ras GTPase-Activating Proteins
  • Protein Kinases
  • Phosphatidylinositol 3-Kinases
  • Phosphotransferases (Alcohol Group Acceptor)
  • Receptors, Platelet-Derived Growth Factor
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases
  • Ptpn11 protein, rat
  • Ptpn6 protein, rat
  • Type C Phospholipases
  • Phospholipase C gamma
Topics
  • Animals
  • Cell Division (genetics)
  • Enzyme Activation
  • GTPase-Activating Proteins
  • Intracellular Signaling Peptides and Proteins
  • Isoenzymes (metabolism)
  • Mutation
  • Neurites
  • PC12 Cells
  • Phosphatidylinositol 3-Kinases
  • Phospholipase C gamma
  • Phosphotransferases (Alcohol Group Acceptor) (metabolism)
  • Platelet-Derived Growth Factor (pharmacology)
  • Protein Kinases (metabolism)
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases (metabolism)
  • Proteins (metabolism)
  • Rats
  • Receptors, Platelet-Derived Growth Factor (genetics, physiology)
  • Signal Transduction
  • Type C Phospholipases (metabolism)
  • ras GTPase-Activating Proteins

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