scholarly journals EGF hijacks miR-198/FSTL1 wound-healing switch and steers a two-pronged pathway toward metastasis

2017 ◽  
Vol 214 (10) ◽  
pp. 2889-2900 ◽  
Author(s):  
Gopinath M. Sundaram ◽  
Hisyam M. Ismail ◽  
Mohsin Bashir ◽  
Manish Muhuri ◽  
Candida Vaz ◽  
...  
Keyword(s):  
Wound Healing ◽  
Wound Closure ◽  
Prognostic Significance ◽  
Competitive Inhibitor ◽  
Molecular Switch ◽  
Extracellular Signal Regulated Kinase ◽  
Keratinocyte Migration ◽  
Extracellular Signal ◽  
Single Transcript ◽  
Kinase Phosphorylation

Epithelial carcinomas are well known to activate a prolonged wound-healing program that promotes malignant transformation. Wound closure requires the activation of keratinocyte migration via a dual-state molecular switch. This switch involves production of either the anti-migratory microRNA miR-198 or the pro-migratory follistatin-like 1 (FSTL1) protein from a single transcript; miR-198 expression in healthy skin is down-regulated in favor of FSTL1 upon wounding, which enhances keratinocyte migration and promotes re-epithelialization. Here, we reveal a defective molecular switch in head and neck squamous cell carcinoma (HNSCC). This defect shuts off miR-198 expression in favor of sustained FSTL1 translation, driving metastasis through dual parallel pathways involving DIAPH1 and FSTL1. DIAPH1, a miR-198 target, enhances directional migration through sequestration of Arpin, a competitive inhibitor of Arp2/3 complex. FSTL1 blocks Wnt7a-mediated repression of extracellular signal–regulated kinase phosphorylation, enabling production of MMP9, which degrades the extracellular matrix and facilitates metastasis. The prognostic significance of the FSTL1-DIAPH1 gene pair makes it an attractive target for therapeutic intervention.

scholarly journals Extracellular Signal-Regulated Kinase/Mitogen-Activated Protein Kinase Regulates Actin Organization and Cell Motility by Phosphorylating the Actin Cross-Linking Protein EPLIN

2007 ◽  
Vol 27 (23) ◽  
pp. 8190-8204 ◽  
Author(s):  
Mei-Ying Han ◽  
Hidetaka Kosako ◽  
Toshiki Watanabe ◽  
Seisuke Hattori
Keyword(s):  
Wound Healing ◽  
Cell Migration ◽  
Cell Motility ◽  
Stress Fiber ◽  
Mitogen Activated Protein Kinase ◽  
Cross Linking ◽  
Intact Cells ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal

ABSTRACT Extracellular signal-regulated kinase (ERK) is important for various cellular processes, including cell migration. However, the detailed molecular mechanism by which ERK promotes cell motility remains elusive. Here we characterize epithelial protein lost in neoplasm (EPLIN), an F-actin cross-linking protein, as a novel substrate for ERK. ERK phosphorylates Ser360, Ser602, and Ser692 on EPLIN in vitro and in intact cells. Phosphorylation of the C-terminal region of EPLIN reduces its affinity for actin filaments. EPLIN colocalizes with actin stress fibers in quiescent cells, and stimulation with platelet-derived growth factor (PDGF) induces stress fiber disassembly and relocalization of EPLIN to peripheral and dorsal ruffles, wherein phosphorylation of Ser360 and Ser602 is observed. Phosphorylation of these two residues is also evident during wound healing at the leading edge of migrating cells. Moreover, expression of a non-ERK-phosphorylatable mutant, but not wild-type EPLIN, prevents PDGF-induced stress fiber disassembly and membrane ruffling and also inhibits wound healing and PDGF-induced cell migration. We propose that ERK-mediated phosphorylation of EPLIN contributes to actin filament reorganization and enhanced cell motility.

scholarly journals Periplaneta americana Extracts Promote Skin Wound Healing via Nuclear Factor Kappa B Canonical Pathway and Extracellular Signal-Regulated Kinase Signaling

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Qin Song ◽  
Qiheng Gou ◽  
Yuxin Xie ◽  
Zhen Zhang ◽  
Chaomei Fu
Keyword(s):  
Wound Healing ◽  
Molecular Mechanisms ◽  
Periplaneta Americana ◽  
Nuclear Factor Kappa B ◽  
Nuclear Translocation ◽  
Nuclear Factor ◽  
Protective Function ◽  
Extracellular Signal Regulated Kinase ◽  
Nuclear Factor Kappa ◽  
Extracellular Signal

Periplaneta americana extracts (PAEs) exhibit wound healing properties. However, the underlying molecular mechanisms are not well understood. Here, we treated human skin fibroblasts (HSF) with PAE and the proliferation was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The wound healing and transwell migration assays were used to detect cell migration. Nuclear factor kappa B (NF-κB) and extracellular signal-regulated kinase (ERK) pathways were analyzed by Western blot (WB). Immunofluorescence staining was used to detect the key molecular localization in the cells. The results showed that PAE enhanced the proliferation and migration of HSF cells. The expression and activation of key proteins such as RelA and p-ERK were increased in NF-κB and ERK pathways followed by nuclear translocation. In vivo, both WB and immunohistochemical (IHC) staining showed that PAE enhanced p-IκBα and p-ERK activation and the nuclear translocation of RelA. Our study suggests that the protective function of PAE is mediated via enhanced NF-κB and ERK signaling.

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