A-Raf associates with and regulates platelet-derived growth factor receptor signalling.
Raf kinases are important intermediates in epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) mediated activation of the mitogen-activated protein kinase (MAPK) pathway. In this report, we show that the A-Raf kinase is associated with activated EGF receptor complexes and with PDGF receptor (PDGFR) complexes independent of prior PDGF treatment. The ability of A-Raf to associate with receptor tyrosine kinases could provide a Ras-GTP-independent mechanism for the membrane localization of A-Raf. Expression of a partially activated A-Raf mutant resulted in decreased tyrosine phosphorylation of the PDGFR, specifically on Y857 (autophosphorylation site) and Y1021 (phospholipase Cgamma1 (PLCgamma1) binding site), but not the binding sites for other signalling proteins (Nck, phosphatidylinositol 3'-kinase (PI3K), RasGAP, Grb2, SHP). Activated A-Raf expression also altered the activation of PLCgamma1, and p85-associated PI3K. Thus, A-Raf can regulate PLCgamma1 signalling via a PDGFR-dependent mechanism and may also regulate PI3K signalling via a PDGFR-independent mechanism.
Mahon
Elizabeth S
ES
Department of Biochemistry, University of Saskatchewan, 107 Wiggins Ave., Saskatoon, Saskatchewan, Canada S7N 5E5.
Hawrysh
Andrea D
AD
Chagpar
Ryaz B
RB
Johnson
Lindsey M
LM
Anderson
Deborah H
DH
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D009928:Organ Specificity; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051966:Phospholipase C gamma; D010766:Phosphorylation; D048491:Proto-Oncogene Proteins A-raf / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019908:Proto-Oncogene Proteins c-raf / Q000096:biosynthesis; D017479:Receptors, Platelet-Derived Growth Factor / Q000502:physiology*; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000378:metabolism
D066246:ErbB Receptors; D019869:Phosphatidylinositol 3-Kinases; D051966:Phospholipase C gamma; D048491:Proto-Oncogene Proteins A-raf; D019908:Proto-Oncogene Proteins c-raf; D017479:Receptors, Platelet-Derived Growth Factor; D010738:Type C Phospholipases