Abstract
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 PDGF β-receptor (PDGFRβ) through multiple autophosphorylation sites, i.e. Tyr-579, Tyr-581, Tyr-740, and Tyr-1021. Using low molecular weight inhibitors, we found that PDGF-BB-induced Fer activation is dependent on PDGFRβ kinase activity, but not on the enzymatic activity of Src or Jak kinases. In cells in which Fer was down-regulated 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 suggest a critical role of Fer in PDGF-BB-induced STAT3 activation and cell transformation.
Keywords:
Animal Models; Growth Factors; Protein-tyrosine Kinase (Tyrosine Kinase); Receptor Tyrosine Kinase; STAT3; Tumor.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Angiogenesis Inducing Agents / pharmacology*
-
Animals
-
Becaplermin
-
Cell Line, Tumor
-
Cell Movement / drug effects*
-
Cell Movement / genetics
-
Cell Proliferation / drug effects*
-
Cell Transformation, Neoplastic / genetics
-
Cell Transformation, Neoplastic / metabolism
-
Cell Transformation, Neoplastic / pathology
-
Enzyme Activation / drug effects
-
Gene Expression Regulation, Enzymologic / drug effects
-
Gene Expression Regulation, Enzymologic / genetics
-
Gene Expression Regulation, Neoplastic / drug effects
-
Gene Expression Regulation, Neoplastic / genetics
-
Humans
-
MAP Kinase Signaling System / drug effects
-
MAP Kinase Signaling System / genetics
-
Mice
-
Mitogen-Activated Protein Kinase 3 / genetics
-
Mitogen-Activated Protein Kinase 3 / metabolism
-
NIH 3T3 Cells
-
Neoplasms / genetics
-
Neoplasms / metabolism*
-
Neoplasms / pathology
-
Phosphorylation / drug effects
-
Phosphorylation / genetics
-
Protein-Tyrosine Kinases / biosynthesis*
-
Protein-Tyrosine Kinases / genetics
-
Proto-Oncogene Proteins c-sis / pharmacology*
-
Receptor, Platelet-Derived Growth Factor beta / genetics
-
Receptor, Platelet-Derived Growth Factor beta / metabolism
-
STAT3 Transcription Factor / genetics
-
STAT3 Transcription Factor / metabolism*
-
STAT5 Transcription Factor / genetics
-
STAT5 Transcription Factor / metabolism
-
src-Family Kinases / genetics
-
src-Family Kinases / metabolism
Substances
-
Angiogenesis Inducing Agents
-
Proto-Oncogene Proteins c-sis
-
STAT3 Transcription Factor
-
STAT5 Transcription Factor
-
Stat3 protein, mouse
-
proto-oncogene protein c-fes-fps
-
Becaplermin
-
Protein-Tyrosine Kinases
-
Receptor, Platelet-Derived Growth Factor beta
-
src-Family Kinases
-
Mitogen-Activated Protein Kinase 3