Vimentin–ERK Signaling Uncouples Slug Gene Regulatory Function

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334

264

Vimentin has been shown to be involved in wound healing, but its functional contribution to this process is poorly understood. Here we describe a previously unrecognized function of vimentin in coordinating fibroblast proliferation and keratinocyte differentiation during wound healing. Loss of vimentin led to a severe deficiency in fibroblast growth, which in turn inhibited the activation of two major initiators of epithelial–mesenchymal transition (EMT), TGF-β1 signaling and the Zinc finger transcriptional repressor protein Slug, in vimentin-deficient (VIM−/−) wounds. Correspondingly, VIM−/− wounds exhibited loss of EMT-like keratinocyte activation, limited keratinization, and slow reepithelialization. Furthermore, the fibroblast deficiency abolished collagen accumulation in the VIM−/− wounds. Vimentin reconstitution in VIM−/− fibroblasts restored both their proliferation and TGF-β1 production. Similarly, restoring paracrine TGF-β–Slug–EMT signaling reactivated the transdifferentiation of keratinocytes, reviving their migratory properties, a critical feature for efficient healing. Our results demonstrate that vimentin orchestrates the healing by controlling fibroblast proliferation, TGF-β1–Slug signaling, collagen accumulation, and EMT processing, all of which in turn govern the required keratinocyte activation.

Section: Wounds Vimentin Reconstitution In Vimmentioning

confidence: 76%

Vimentin coordinates fibroblast proliferation and keratinocyte differentiation in wound healing via TGF-β–Slug signaling

Cheng

Shen

Mohanasundaram

et al. 2016

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334

264

“…We demonstrated that FiVe1 fully inhibited VIM-dependent cellular motility in scratch assays. VIM knockdown in post-EMT cells has been demonstrated to reorganize cellular morphology and inhibit migratory capacity, underscoring the notion that targeting VIM can antagonize EMT-induced CSC traits (39).…”

Section: Discussionmentioning

confidence: 87%

A vimentin binding small molecule leads to mitotic disruption in mesenchymal cancers

Bollong

Pietilä

Pearson

et al. 2017

Expression of the transcription factor FOXC2 is induced and necessary for successful epithelial-mesenchymal transition, a developmental program that when activated in cancer endows cells with metastatic potential and the properties of stem cells. As such, identifying agents that inhibit the growth of FOXC2-transformed cells represents an attractive approach to inhibit chemotherapy resistance and metastatic dissemination. From a high throughput synthetic lethal screen, we identified a small molecule, FiVe1, which selectively and irreversibly inhibits the growth of mesenchymally transformed breast cancer cells and soft tissue sarcomas of diverse histological subtypes. FiVe1 targets the intermediate filament and mesenchymal marker vimentin (VIM) in a mode which promotes VIM disorganization and phosphorylation during metaphase, ultimately leading to mitotic catastrophe, multinucleation, and the loss of stemness. These findings illustrate a previously undescribed mechanism for interrupting faithful mitotic progression and may ultimately inform the design of therapies for a broad range of mesenchymal cancers.vimentin | epithelial-to-mesenchymal transition | cancer stem cell | mitosis | drug discovery F or many tumor types, resistance to conventional chemotherapy and subsequent tumor relapse have been attributed to the presence of a slower cycling, drug-resistant population of cells termed cancer stem cells (CSCs) or tumor initiating cells. We and others have demonstrated that activation of a latent embryonic program, called the epithelial-mesenchymal transition (EMT), endows epithelial-derived cancer cells with the properties of stem cells as well as migratory and metastatic potential (1). Cells undergoing EMT exhibit the loss of epithelial cell-cell contacts (e.g., E-cadherin), the induction of matrix degrading proteases (e.g., matrix metalloproteinases), and the acquisition of motility-inducing intermediate filaments [e.g., vimentin (VIM)], features which promote metastatic progression by allowing dissemination from the local tumor niche (2). A number of transcription factors (e.g., Snail, Twist, ZEB1) and microenvironment-derived extracellular signaling molecules (e.g., TGF-β1) are capable of inducing the EMT transcriptional program. Among these factors, we have demonstrated that the transcription factor Forkhead Box C2 (FOXC2) is a central regulator of EMT in breast cancer (3, 4). FOXC2 expression is both up-regulated and required for the induction of CSC properties by the classical EMT-inducing factors Twist, Snail, and TGF-β1 (4

“…The view that vimentin potentiates Jagged function is corroborated by the data showing that Jagged expression correlates with vimentin expression in several tissues and in cancer, in particular. Elevated expression of both vimentin and Jagged has been implicated in tumor progression (6,8,10,16,(73)(74)(75)(76). Furthermore, observations in vimentin knockout mice links vimentin to defects in wound healing, fibrosis, inflammation, epidermal aging, and epithelial mesenchymal transition in cancer (4,7,8).…”

Section: Discussionmentioning

confidence: 99%

“…Whereas IFs provide cells with mechanical stability, there is mounting evidence indicating that IFs are involved in a range of metabolic, signaling, and regulatory processes that are unrelated to mechanical functions (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). The vimentin IF has been shown to act as a scaffold for signaling proteins that regulate epithelial mesenchymal transition (EMT), cancer cell invasion, wound healing and tissue repair, tissue aging, as well as inflammatory signaling (3,4,(6)(7)(8)10). Vimentin anchors and organizes adhesion molecules as well as actomyosin complexes (15) to regulate cell adhesion and migration (4,5).…”

mentioning

confidence: 99%

“…Vimentin anchors and organizes adhesion molecules as well as actomyosin complexes (15) to regulate cell adhesion and migration (4,5). Vimentin also influences protein function through regulation of protein trafficking and is involved in the regulation of gene expression (7,8,10,(16)(17)(18). Vimentin, thus, has regulatory functions especially in dynamic cellular processes.…”

mentioning

confidence: 99%

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Selective regulation of Notch ligands during angiogenesis is mediated by vimentin

Antfolk

Sjöqvist

Cheng

et al. 2017

Self Cite

Notch signaling is a key regulator of angiogenesis, in which sprouting is regulated by an equilibrium between inhibitory Dll4-Notch signaling and promoting Jagged-Notch signaling. Whereas Fringe proteins modify Notch receptors and strengthen their activation by Dll4 ligands, other mechanisms balancing Jagged and Dll4 signaling are yet to be described. The intermediate filament protein vimentin, which has been previously shown to affect vascular integrity and regenerative signaling, is here shown to regulate ligand-specific Notch signaling. Vimentin interacts with Jagged, impedes basal recycling endocytosis of ligands, but is required for efficient receptor ligand transendocytosis and Notch activation upon receptor binding. Analyses of Notch signal activation by using chimeric ligands with swapped intracellular domains (ICDs), demonstrated that the Jagged ICD binds to vimentin and contributes to signaling strength. Vimentin also suppresses expression of Fringe proteins, whereas depletion of vimentin enhances Fringe levels to promote Dll4 signaling. In line with these data, the vasculature in vimentin knockout (VimKO) embryos and placental tissue is underdeveloped with reduced branching. Disrupted angiogenesis in aortic rings from VimKO mice and in endothelial 3D sprouting assays can be rescued by reactivating Notch signaling by recombinant Jagged ligands. Taken together, we reveal a function of vimentin and demonstrate that vimentin regulates Notch ligand signaling activities during angiogenesis.