期刊
GROWTH FACTORS
卷 30, 期 4, 页码 220-229出版社
TAYLOR & FRANCIS LTD
DOI: 10.3109/08977194.2012.683189
关键词
EGFR; Stat3; dynamin; Erk1/2; endocytosis
资金
- National Health and Medical Research Council (NHMRC)
- University of Melbourne
Signalling from receptor tyrosine kinases is elicited by ligand binding which initiates the activation of many downstream signalling cascades. Endocytosis has been widely accepted as one mechanism in which cells inactivate signalling by internalising and subsequently degrading activated receptors. However, it is now evident that endocytosis of signalling receptors is important in initiation and sustaining downstream signalling. We and others have previously shown that epidermal growth factor receptor (EGFR) overexpression and activation of signal transducer and activator of transcription 3 (Stat3) are associated with tumourigenicity. Here, we examine the role of endocytosis in EGFR signal attenuation and differential signalling. Inhibition of dynamin II (Dyn II), a GTPase required for endocytosis, with a small molecular weight inhibitor, led to reduced EGF-mediated Stat3 phosphorylation and transcriptional activity in the A431 and HN5 human tumour cell lines. However, Dyn II inhibition had minimal effect on EGF-mediated EGFR and Erk1/2 phosphorylation, which is often regarded responsible for the tumourigenic function of the EGFR. Interestingly, this effect on Stat3 activation was not due to reduced EGFR/Stat3 association. Likewise, cells transfected with Dyn H siRNA or stably transfected with Dyn II shRNA had reduced EGF-mediated phospho-Stat3 levels but similar EGF-mediated phospho-EGFR and phospho-Erk1/2 levels compared with controls. Dyn II siRNA also reduced Stat3 transcriptional reporter activity and inhibits Stat3 accumulating into the nucleus. Taken together, our data suggest that the activation status of Stat3 and Erk1/2 and the sustainability of these signals are potentially due to the spatial and temporal control of the EGFR within the cell. This notion may have implications on therapeutic targeting and efficacy when using inhibitors to proteins either regulating endocytosis and/or signalling.
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