EGFR-induced cell migration is mediated predominantly by the JAK-STAT pathway in primary esophageal keratinocytes

Gastroenterology Division, Department of Medicine, Abramson Cancer Center and Family Cancer Research Institute, University of Pennsylvania, 415 Curie Blvd., Philadelphia, PA 19104, USA.
AJP Gastrointestinal and Liver Physiology (Impact Factor: 3.8). 01/2005; 287(6):G1227-37. DOI: 10.1152/ajpgi.00253.2004
Source: PubMed


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.

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    • "Furthermore, one of the signaling events implicates tyrosine phosphorylation and activation of STAT3 protein [82]. This is in line with the previous demonstration that EGFR-induced cell migration is mediated predominantly by the STAT-pathway in keratinocytes and that STAT3 plays an essential role for skin remodeling and wound healing [82,83]. Esculentin-1a(1-21)NH 2 Stimulates Migration of Keratinocytes PLOS ONE | DOI:10.1371/journal.pone.0128663 "
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    • "Interestingly, only one metastatic tumour sample (MET_HR_10) shows strong loss of expression of ERBB2 (HER2), a gene often associated with promoting cell proliferation, particularly in breast cancer [47,48]. It is known, however, that loss of expression of ERBB2 is a feature of metastatic sites in breast cancer that is otherwise ERBB2 positive [49] and further that loss of ERBB2 expression has been strongly associated with progression to metastasis in osteosarcoma [50]. "
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