Networking galore: intermediate filaments and cell migration

Chung, Byung Min; Rotty, Jeremy D.; Coulombe, Pierre A.

doi:10.1016/j.ceb.2013.06.008

Cited by 167 publications

(154 citation statements)

References 107 publications

(126 reference statements)

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“…[33][34][35] In comparison with controls, we found a 39-fold increase in the P-vim content in PAH lungs, a 152-fold increase in P-vim in the MCT-exposed lungs, and a 3.25-fold increase in P-vim in the lungs of BMPR2 Δ140Ex1/+ rats. Accordingly, we found by CLEM a 6.6-and 5.1-fold increase in P-vim density in luminal ECs and SECs, respectively, in intimal lesions in comparison with control pulmonary arteries.…”

Section: Bmpr2mentioning

confidence: 68%

Endothelial-to-Mesenchymal Transition in Pulmonary Hypertension

et al. 2015

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P ulmonary arterial hypertension (PAH) is a rare disorder, with a prevalence of 15 to 50 patients per million in the population. It is characterized by remodeling of the precapillary pulmonary arteries, with endothelial cell dysfunction contributing to endothelial and pulmonary artery smooth muscle cell proliferation. This remodeling increases pulmonary vascular resistance and pulmonary arterial pressure (mean pulmonary arterial pressure ≥25 mm Hg and a pulmonary capillary wedge Background-The vascular remodeling responsible for pulmonary arterial hypertension (PAH) involves predominantly the accumulation of α-smooth muscle actin-expressing mesenchymal-like cells in obstructive pulmonary vascular lesions. Endothelial-to-mesenchymal transition (EndoMT) may be a source of those α-smooth muscle actin-expressing cells. Methods and Results-In situ evidence of EndoMT in human PAH was obtained by using confocal microscopy of multiple fluorescent stainings at the arterial level, and by using transmission electron microscopy and correlative light and electron microscopy at the ultrastructural level. Findings were confirmed by in vitro analyses of human PAH and control cultured pulmonary artery endothelial cells. In addition, the mRNA and protein signature of EndoMT was recognized at the arterial and lung level by quantitative real-time polymerase chain reaction and Western blot analyses. We confirmed our human observations in established animal models of pulmonary hypertension (monocrotaline and SuHx). After establishing the first genetically modified rat model linked to BMPR2 mutations (BMPR2 Δ140Ex1/+ rats), we demonstrated that EndoMT is linked to alterations in signaling of BMPR2, a gene that is mutated in 70% of cases of familial PAH and in 10% to 40% of cases of idiopathic PAH. We identified molecular actors of this pathological transition, including twist overexpression and vimentin phosphorylation. We demonstrated that rapamycin partially reversed the protein expression patterns of EndoMT, improved experimental PAH, and decreased the migration of human pulmonary artery endothelial cells, providing the proof of concept that EndoMT is druggable. Conclusions-EndoMT is linked to alterations in BPMR2 signaling and is involved in the occlusive vas cular remodeling of PAH, findings that may have therapeutic implications.

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Section: Bmpr2mentioning

confidence: 68%

Endothelial-to-Mesenchymal Transition in Pulmonary Hypertension

et al. 2015

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“…The role of vimentin in cell motility has been well demonstrated previously. Merely the presence of vimentin has been shown to promote cell motility (Chung et al, 2013). A recent hypothesis suggests that vimentin maintains the directionality of a cell that has already committed to migrate (Chernoivanenko et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…1A-C), and it is well known that vimentin regulates cell motility (Chung et al, 2013), we hypothesized that these lipids might regulate vimentin. Phosphorylation is one of the primary posttranslational modifications (PTM) regulating vimentin organisation (Hyder et al, 2008;Izawa and Inagaki, 2006).…”

Section: Sphingolipids Induce Phosphorylation Of Vimentin On S71mentioning

confidence: 99%

“…Vimentin expression is associated with metastatic ability and it is widely accepted to be important for migratory functions (Chung et al, 2013;Nieminen et al, 2006). One key way that vimentin regulates cell motility is through dynamic reorganisation of its constituent filament network, which is regulated by phosphorylation on the N-terminus (Hyder et al, 2008;Ivaska et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Sphingolipids inhibit vimentin-dependent cell migration

Hyder

Kemppainen

Isoniemi

et al. 2015

Journal of Cell Science

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The sphingolipids, sphingosine 1-phosphate (S1P) and sphingosylphosphorylcholine (SPC), can induce or inhibit cellular migration. The intermediate filament protein vimentin is an inducer of migration and a marker for epithelial-mesenchymal transition. Given that keratin intermediate filaments are regulated by SPC, with consequences for cell motility, we wanted to determine whether vimentin is also regulated by sphingolipid signalling and whether it is a determinant for sphingolipid-mediated functions. In cancer cells where S1P and SPC inhibited migration, we observed that S1P and SPC induced phosphorylation of vimentin on S71, leading to a corresponding reorganization of vimentin filaments. These effects were sphingolipid-signalling-dependent, because inhibition of either the S1P 2 receptor (also known as S1PR2) or its downstream effector Rho-associated kinase (ROCK, for which there are two isoforms ROCK1 and ROCK2) nullified the sphingolipid-induced effects on vimentin organization and S71 phosphorylation. Furthermore, the anti-migratory effect of S1P and SPC could be prevented by expressing S71-phosphorylation-deficient vimentin. In addition, we demonstrated, by using wild-type and vimentin-knockout mouse embryonic fibroblasts, that the sphingolipid-mediated inhibition of migration is dependent on vimentin. These results imply that this newly discovered sphingolipid-vimentin signalling axis exerts brake-and-throttle functions in the regulation of cell migration.

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“…46 Under non-cancerous conditions, vimentin is involved in processes that require cell migration, such as wound healing, where it has a pivotal role in determining cell polarity, regulation of cell-to-cell contact and transport of signalling proteins. 47 It therefore seems likely that altered expression of this molecule in cancerous tissue may also affect cell-cell adhesion and cell polarity, enabling cells to detach from the primary tumour and invade the surrounding stroma. 56 ), it is evident that for cells to colonise a distant site, such as bone, they must undergo the reverse process of epithelial-to-mesenchymal transition (MET) while still retaining a population of cancer stem cells capable of inducing the metastatic tumour.…”

Section: Vimentinmentioning

confidence: 99%

Molecular alterations that drive breast cancer metastasis to bone

2015

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Epithelial cancers including breast and prostate commonly progress to form incurable bone metastases. For this to occur, cancer cells must adapt their phenotype and behaviour to enable detachment from the primary tumour, invasion into the vasculature, and homing to and subsequent colonisation of bone. It is widely accepted that the metastatic process is driven by the transformation of cancer cells from a sessile epithelial to a motile mesenchymal phenotype through epithelial-mesenchymal transition (EMT). Dissemination of these motile cells into the circulation provides the conduit for cells to metastasise to distant organs. However, accumulating evidence suggests that EMT is not sufficient for metastasis to occur and that specific tissue-homing factors are required for tumour cells to lodge and grow in bone. Once tumour cells are disseminated in the bone environment, they can revert into an epithelial phenotype through the reverse process of mesenchymal-epithelial transition (MET) and form secondary tumours. In this review, we describe the molecular alterations undertaken by breast cancer cells at each stage of the metastatic cascade and discuss how these changes facilitate bone metastasis.

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Networking galore: intermediate filaments and cell migration

Cited by 167 publications

References 107 publications

Endothelial-to-Mesenchymal Transition in Pulmonary Hypertension

Endothelial-to-Mesenchymal Transition in Pulmonary Hypertension

Sphingolipids inhibit vimentin-dependent cell migration

Molecular alterations that drive breast cancer metastasis to bone

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