The Fer tyrosine kinase is important for platelet-derived growth factor-BB-induced Stat3 phosphorylation, colony formation in soft agar and tumor growth in vivo.
Fer is a cytoplasmic tyrosine kinase that is activated in response to platelet-derived growth factor (PDGF) stimulation. In the present report, we show that Fer associates with the activated PDGFbeta receptor (PDGFRbeta) through multiple autophosphorylation sites, i.e. Tyr579, Tyr581, Tyr740 and Tyr1021. Using low molecular weight inhibitors, we found that PDGF-BB-induced Fer activation is dependent on PDGFRbeta kinase activity, but not on the enzymatic activity of Src or Jak kinases. In cells in which Fer was downregulated using siRNA, PDGF-BB was unable to induce phosphorylation of Stat3, whereas phosphorylations of Stat5, Erk1/2 and Akt were unaffected. PDGF-BB-induced activation of Stat3 occurred also in cells expressing kinase-dead Fer, suggesting a kinase-independent adaptor role of Fer. Expression of Fer was dispensable for PDGF-BB-induced proliferation and migration, but essential for colony formation in soft agar. Tumor growth in vivo was delayed in cells depleted of Fer expression. Our data suggests a critical role of Fer in PDGF-BB-induced Stat3 activation and cell transformation.
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PDGF-BB Stat3 Fer PDGFbeta receptor PDGFRbeta tyrosine kinase PDGF-BB Fer PDGFRbeta kinase tyrosine Src Jak kinases Fer PDGF-BB Stat3 Stat5 Erk1/2 Akt PDGF-BB Tyr Stat3 platelet-derived growth factor kinase Fer kinase Fer Fer PDGF-BB Fer platelet-derived growth factor-BB Tyr Fer tyrosine kinase Stat3 Tyr Tyr tyrosine Fer PDGF Fer