STAT activation by the PDGF receptor requires juxtamembrane phosphorylation sites but not Src tyrosine kinase activation

Abstract

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 PDGFtreated 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 su cient 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 ®broblast 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 bPDGF receptor, but that both processes are regulated independently by this region.

Constitutive activation of FLT3 stimulates multiple intracellular signal transducers and results in transformation

“…In these reports, JAK 1, JAK 2, STAT 1, STAT 3 and /or STAT 5 were tyrosine-phosphorylated following receptor activation in response to EGF, PDGF, CSF-1 or SCF stimulation. [65][66][67][68][69][70] These studies, in conjunction with the findings reported here, imply a possible role for the JAK-STAT pathway in FLT3 receptor signaling. Whether this is a result of phosphorylation of JAKs by the activated receptor via a direct interaction of the two proteins or is indirect and results from phosphorylation and activation of other tyrosine kinases (eg SRC family members) or intermediate adaptor proteins is not known and will require further study.…”

Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma

“…It is widely believed that the ability of PDGFs to induce liver fibrosis and neoplastic cell transformation is closely associated with the transcriptional induction of TGFβ, an essential mediator of fibrogenesis [241,242]. TGFβ and PDGFs act through activation of STAT3 [75,76] leading to the upregulation of genes promoting cell proliferation, survival, and cell transformation [77]. The role of TGFβ and PDGF pathways in the induction of liver fibrosis and cirrhosis, and putative contributing events to the neoplastic transformation of hepatocytes [243][244][245][246] is well established.…”

“…STAT proteins are also triggered by receptor tyrosine kinases such as epidermal growth factor-receptor (EGF-R), PDGF-R [69], and colony stimulating factor-1R (CSF-1R) [70], seven transmembrane G-protein-coupled receptors such as angiotensin II receptor [71] and serotonin 5-HT2A receptor [72] and through the T cell receptor complex [73] and the CD40 receptor [74]. EGF, TGFβ, and PDGF receptors are also capable of directly phosphorylating STAT proteins in the absence of JAK activation, leading to the up-regulation of genes that promote cell proliferation, survival, and cell transformation [75][76][77].…”

Tyrosine kinase fusion genes in chronic myeloproliferative diseases

“…Transformation is dependent on a functional PDGFRB tyrosine kinase domain, the presence of the dimerization motif encoded by the partner gene, PDGFRB tyrosines 579/581 and involves both STAT5-dependent and independent pathways. [39][40][41][42] …”