Abstract
The epidermal growth factor receptor (EGFR) activates several signaling cascades in response to epidermal growth factor stimulation. One of these signaling events involves tyrosine phosphorylation of signal transducer and activator of transcription (STAT), whereas another involves activation of the phosphatidylinositol 3-OH kinase pathway. Two possibilities for STAT activation exist: a janus kinase (JAK)-dependent and a JAK-independent mechanism. Herein, we demonstrate that EGFR overexpression in primary esophageal keratinocytes activates STAT in a JAK-dependent fashion with the functional consequence of enhanced cell migration, which can be abolished by use of a JAK-specific inhibitor, AG-490. We determined the mechanisms underlying the signal transduction pathway responsible for increased cell migration. Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2. Thereafter, the STATs translocate to the nucleus within 15 min. In addition, we found that activation of this signaling pathway results in matrix metalloproteinase-1 (MMP-1) activity. By contrast, Akt activation does not impact the EGFR-STATs-JAKs complex formation and nuclear translocation of the STATs with subsequent MMP-1 activity, although Akt activation may contribute to cell migration through an independent mechanism. Taken together, we find that the recruitment of the STAT-JAK complex by EGFR is responsible for keratinocyte migration that, in turn, might be mediated by MMP-1 activation.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Antibodies, Blocking / pharmacology
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Blotting, Western
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Cell Line
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Cell Membrane / drug effects
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Cell Membrane / metabolism
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Cell Movement / drug effects
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Cell Nucleus / drug effects
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Cell Nucleus / metabolism
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Collagen / chemistry
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Collagen / metabolism
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Cytoplasm / drug effects
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Cytoplasm / metabolism
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DNA-Binding Proteins
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Enzyme Inhibitors / pharmacology
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ErbB Receptors / antagonists & inhibitors
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ErbB Receptors / physiology*
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Esophagus / cytology*
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Esophagus / drug effects
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Fluorescent Antibody Technique
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Humans
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Keratinocytes / drug effects*
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Matrix Metalloproteinase 1 / metabolism
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Microscopy, Confocal
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation
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Protein Serine-Threonine Kinases / physiology
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Protein Transport / physiology
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / physiology*
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Proto-Oncogene Proteins / physiology
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Proto-Oncogene Proteins c-akt
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STAT1 Transcription Factor
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STAT3 Transcription Factor
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Signal Transduction / drug effects*
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Trans-Activators
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Tyrphostins / pharmacology
Substances
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Antibodies, Blocking
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DNA-Binding Proteins
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Enzyme Inhibitors
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Proto-Oncogene Proteins
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STAT1 Transcription Factor
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STAT1 protein, human
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STAT3 Transcription Factor
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STAT3 protein, human
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Trans-Activators
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Tyrphostins
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alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
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Collagen
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ErbB Receptors
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Protein-Tyrosine Kinases
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Matrix Metalloproteinase 1