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

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.

Transactivation of Epidermal Growth Factor Receptor Is Involved in Leptin-Induced Activation of Janus-Activated Kinase 2 and Extracellular Signal–Regulated Kinase 1/2 in Human Gastric Cancer Cells

“…In addition, EGFR signals can also induce JAK2 activation (18). Our results were compatible with these previous reports and implied that in various signaling pathways induced by leptin, EGFR transactivation acts upstream of both the JAK2 and ERK signaling pathways.…”

JAK kinases promote invasiveness in VHL-mediated renal cell carcinoma by a suppressor of cytokine signaling-regulated, HIF-independent mechanism

“…The JAK/STAT signaling pathway has been extensively characterized in many systems, including hematopoietic, gastrointestinal, prostate, and vascular endothelial cells (2,4,5,17). In the context of cancers, JAK kinases can activate STATs, as well as many other signals, to promote cell survival and proliferation.…”

Cell autonomous roles for AP‐2α in lens vesicle separation and maintenance of the lens epithelial cell phenotype

“…These data are consistent with the processes of lens vesicle separation and lens epithelial/fiber cell differentiation that are disrupted in the Le-AP-2␣ mutant mice. Furthermore, stratification of these data into molecular function indicated that the majority of genes differentially regulated between normal and mutant lenses lacking AP-2␣ in the lens, reside in the epidermal growth factor receptor (Egfr) and Janus kinase (Jak) signal transduction cascades, pathways previously implicated in cell differentiation and cellular migration during development (Kumar and Moses, 2001;Andl et al, 2004;Brown et al, 2006).…”