Epidermal growth factor receptor-mediated motility in fibroblasts

Wells, Alan; Gupta, Kiran; Chang, Philip; Swindle, Scott; Glading, Angela; Shiraha, Hidenori

doi:10.1002/(sici)1097-0029(19981201)43:5<395::aid-jemt6>3.0.co;2-t

Cited by 89 publications

(57 citation statements)

References 150 publications

(176 reference statements)

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“…In some systems, these processes are also dependent on activated MAPK (Verbeek et al, 1998;Wells et al, 1998). We demonstrate here that EGF as well as FCS caused a marked stimulation of cell migration, which was highly dependent on activated MEK.…”

Section: Discussionmentioning

confidence: 55%

Growth factor-dependent activation of the Ras-Raf-MEK-MAPK pathway in the human pancreatic carcinoma cell line PANC-1 carrying activated K-ras: implications for cell proliferation and cell migration

et al. 2000

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Section: Discussionmentioning

confidence: 55%

Growth factor-dependent activation of the Ras-Raf-MEK-MAPK pathway in the human pancreatic carcinoma cell line PANC-1 carrying activated K-ras: implications for cell proliferation and cell migration

et al. 2000

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“…However recently, Sonnenburg et al (72) have shown that PDK1 may phosphorylate cPKC by a PI3K-independent mechanism (72). This other pathway might also control EGFinduced PKC␦ phosphorylation in our cells; as the multiple stimulatory molecules in serum are distinct from EGFR ligands, discrepancies in upstream signaling pathways between serum and EGF are not unexpected (6). Regardless, the mechanism by which the late phase of PKC␦ activation occurs remains to be determined in subsequent studies.…”

Section: Fig 8 Lack Of Plc Signaling Correlates With Delayed Phosphmentioning

confidence: 80%

Epidermal Growth Factor Induces Fibroblast Contractility and Motility via a Protein Kinase C δ-dependent Pathway

Iwabu

Smith

Allen

et al. 2004

Journal of Biological Chemistry

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Myosin-based cell contractile force is considered to be a critical process in cell motility. However, for epidermal growth factor (EGF)-induced fibroblast migration, molecular links between EGF receptor (EGFR) activation and force generation have not been clarified. Herein, we demonstrate that EGF stimulation increases myosin light chain (MLC) phosphorylation, a marker for contractile force, concomitant with protein kinase C (PKC) activity in mouse fibroblasts expressing human EGFR constructs. Interestingly, PKC␦ is the most strongly phosphorylated isoform, and the preferential PKC␦ inhibitor rottlerin largely prevented EGF-induced phosphorylation of PKC substrates and MARCKS. The pathway through which EGFR activates PKC␦ is suggested by the fact that the MEK-1 inhibitor U0126 and the phosphatidylinositol 3-kinase inhibitor LY294002 had no effect on PKC␦ activation, whereas lack of PLC␥ signaling resulted in delayed PKC␦ activation. EGF-enhanced MLC phosphorylation was prevented by a specific MLC kinase inhibitor ML-7 and the PKC inhibitors chelerythrine chloride and rottlerin. Further indicating that PKC␦ is required, a dominant-negative PKC␦ construct or RNAi-mediated PKC␦ depletion also prevented MLC phosphorylation. In the absence of PLC signaling, MLC phosphorylation and cell force generation were delayed similarly to PKC␦ activation. All of the interventions that blocked PKC␦ activation or MLC phosphorylation abrogated EGF-induced cell contractile force generation and motility. Our results suggest that PKC␦ activation is responsible for a major part of EGF-induced fibroblast contractile force generation. Hence, we identify here a new pathway helping to govern cell motility, with PLC signaling playing a role in activation of PKC␦ to promote the acute phase of EGF-induced MLC activation.Cell motility induced by activation of epidermal growth factor receptor (EGFR), 1 and related receptor tyrosine kinases, can be deconstructed into a series of orchestrated events: lamellipodial extension, formation of forward adhesions, exertion of contractile forces to pull the cell body forward, and detachment of the rear (1). While each process is required for net cell locomotion, it is not necessarily the case that signals downstream of receptor activation must concomitantly be involved in triggering all of the processes. Despite longstanding anecdotal indications, only recently have formal demonstrations emerged that signaling via EGFR actually elicits cell contractile force generation (2, 3) along with the other biophysical processes (4 -6). Because of the central importance of growth factor-induced cell motility in physiological and pathological applications, such as organogenesis, wound repair, and tumor invasion, determination of key pathways involved in connecting EGFR activity to contractile force generation, as well as the other processes underlying motility, is a crucial undertaking. Myosin motors operating on cytoskeletal actin filaments are presumed to be involved in growth factor-induced cell motility in manne...

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“…Several ligands can bind to and activate EGFR, including EGF, TGF-α, heparin-binding EGF-like growth factor (HB-EGF), amphiregulin, betacellulin, and epiregulin (EREG) (9). The downstream effects of EGFR are mediated by a number of important signaling pathways, including MAPK (8) and PI3K/AKT/mTOR -which are known to regulate pain (12)(13)(14). EGFR has been shown to affect receptors important for pain processing, including opioid receptors (15), β-adrenergic receptors (16), cannabinoid type 1 (CB1), and transient receptor potential cation channel, subfamily V, member 1 (TRPV1) receptors (17).…”

Section: Introductionmentioning

confidence: 99%