STAT activation by the PDGF receptor requires juxtamembrane phosphorylation sites but not Src tyrosine kinase activation.
Activation of the platelet-derived growth factor (PDGF) receptor tyrosine kinase induces tyrosine phosphorylation of Signal Transducer and Activator of Transcription (STAT) proteins. Since the PDGF receptor also activates the Src tyrosine kinase, it is possible that Src mediates tyrosine phosphorylation of STATs in PDGF-treated cells. Consistent with a role for Src in STAT activation, we found that a PDGF receptor juxtamembrane tyrosine residue required for Src activation is necessary and sufficient for activation of STATs 1 and 3. To test the Src requirement further, we made other mutations in the PDGF receptor juxtamembrane region that increased or decreased Src binding. In epithelial and fibroblast cells, PDGF activated STAT1, 3 and 6 in the absence of detectable binding and activation of Src. In addition, PDGF induced c-myc RNA expression and DNA synthesis even though Src was not detectably activated. The activation of MAP kinase and the induction of c-fos gene expression both correlated with STAT but not Src activation by the receptor. We conclude that juxtamembrane tyrosine phosphorylation is necessary for both Src tyrosine kinase and STAT activation by the betaPDGF receptor, but that both processes are regulated independently by this region.
Sachsenmaier
C
C
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Sadowski
H B
HB
Cooper
J A
JA
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D016762:Genes, fos / Q000235:genetics; D016259:Genes, myc / Q000235:genetics; D006801:Humans; D051379:Mice; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000235:genetics / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta; D016184:Receptors, Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism*
D004268:DNA-Binding Proteins; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D016184:Receptors, Colony-Stimulating Factor; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D019000:Phosphotyrosine; D004247:DNA; D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor; D019061:src-Family Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases