Stathmin Regulates Keratinocyte Proliferation and Migration during Cutaneous Regeneration

Schmitt, Sabrina; Safferling, Kai; Westphal, Kathi; Hrabowski, Manuel; Müller, Ute; Angel, Peter; Wiechert, Lars; Ehemann, Volker; Müller, Bettina; Holland‐Cunz, Stefan; Stichel, Damian; Harder, Nathalie; Rohr, Karl; Germann, Günter; Matthäus, Franziska; Schirmacher, Peter; Grabe, Niels; Breuhahn, Kai

doi:10.1371/journal.pone.0075075

Cited by 14 publications

(11 citation statements)

References 33 publications

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“…This raises the question which pathway-specific target genes may facilitate the cellular decision discriminating between proliferation and migration. Stathmin is suggested as a target of the HGF/c-Met signaling axis, which predominantly supports keratinocyte proliferation during wound healing [26]. In our model we also predict the activation of Stathmin (2), linked with endothelial cell migration, in agreement with these findings.…”

Section: Regulatory Pathways In the Mcwalk Extracted Networksupporting

confidence: 84%

Directed random walks and constraint programming reveal active pathways in hepatocyte growth factor signaling

et al. 2015

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An effective means to analyze mRNA expression data is to take advantage of established knowledge from pathway databases, using methods such as pathway-enrichment analyses. However, pathway databases are not casespecific and expression data could be used to infer gene-regulation patterns in the context of specific pathways. In addition, canonical pathways may not always describe the signaling mechanisms properly, because interactions can frequently occur between genes in different pathways. Relatively few methods have been proposed to date for generating and analyzing such networks, preserving the causality between gene interactions and reasoning over the qualitative logic of regulatory effects. We present an algorithm (MCWalk) integrated with a logic programming approach, to discover subgraphs in large-scale signaling networks by random walks in a fully automated pipeline. As an exemplary application, we uncover the signal transduction mechanisms in a gene interaction network describing hepatocyte growth factor-stimulated cell migration and proliferation from geneexpression measured with microarray and RT-qPCR using in-house perturbation experiments in a keratinocyte-fibroblast co-culture. The resulting subgraphs illustrate possible associations of hepatocyte growth factor receptor c-Met nodes, differentially expressed genes and cellular states. Using perturbation experiments and Answer Set programming, we are able to select those which are more consistent with the experimental data. We discover key regulator nodes by measuring the frequency with which they are traversed when connecting signaling between receptors and significantly regulated genes and predict their expression-shift consistently with the measured data. The Java implementation of MCWalk is publicly available under the MIT license at: https://bitbucket.org/akittas/biosubg.

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Section: Regulatory Pathways In the Mcwalk Extracted Networksupporting

confidence: 84%

Directed random walks and constraint programming reveal active pathways in hepatocyte growth factor signaling

et al. 2015

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“…Rac1 activation also results in phosphorylation of stathmin, thereby impairing its microtubule catastrophe–promoting properties and modulating keratinocyte forward movements during epidermal repair ( Gupta et al. , 2013 ; Schmitt et al. , 2013 ).…”

Section: Discussionmentioning

confidence: 99%

An ELMO2-RhoG-ILK network modulates microtubule dynamics

Jackson

Ivanova

Dagnino

2015

MBoC

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“…This is expected since stathmin is active at the cell rear, the hotspot for the unstable MTs needed for motility facilitated by actomyosin contraction. 57 In contrast, MCAK, a member of the MT depolymerizing kinesin 13s, has an interesting effect on cell migration: both its overexpression and knockdown impair endothelial cell movement. MCAK is mainly spatially inhibited when on the tips of MTs at the cell front, suggesting that there is a fine balance between its localization and activity to ensure proper cell motility.…”

Section: Role Of Mt Destabilizers In Cell Migrationmentioning

confidence: 99%

Targeting Microtubules for Wound Repair

Charafeddine

Nosanchuk

Sharp

2016

Advances in Wound Care

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Significance: Fast and seamless healing is essential for both deep and chronic wounds to restore the skin and protect the body from harmful pathogens. Thus, finding new targets that can both expedite and enhance the repair process without altering the upstream signaling milieu and causing serious side effects can improve the way we treat wounds. Since cell migration is key during the different stages of wound healing, it presents an ideal process and intracellular structural machineries to target. Recent Advances and Critical Issues: The microtubule (MT) cytoskeleton is rising as an important structural and functional regulator of wound healing. MTs have been reported to play different roles in the migration of the various cell types involved in wound healing. Specific microtubule regulatory proteins (MRPs) can be targeted to alter a section or subtype of the MT cytoskeleton and boost or hinder cell motility. However, inhibiting intracellular components can be challenging in vivo, especially using unstable molecules, such as small interfering RNA. Nanoparticles can be used to protect these unstable molecules and topically deliver them to the wound. Utilizing this approach, we recently showed that fidgetin-like 2, an uncharacterized MRP, can be targeted to enhance cell migration and wound healing. Future Directions: To harness the full potential of the current MRP therapeutic targets, studies should test them with different delivery platforms, dosages, and skin models. Screening for new MT effectors that boost cell migration in vivo would also help find new targets for skin repair.Keywords: microtubules, nanoparticle, siRNA, Fidgetin-like 2, cell migration SCOPE AND SIGNIFICANCEThis review explores the role of microtubules (MTs), a major component of the cell's internal skeleton, in wound healing, especially during cell migration. The structure and function of MTs are spatially and temporally regulated by microtubule regulatory proteins (MRPs), which have diverse effects on cell migration depending on their role and the cell type being targeted. The review also presents alternative techniques to identify and examine new therapeutic wound-healing targets. TRANSLATIONAL RELEVANCEWe recently characterized the role of fidgetin-like 2 (FL2), a novel MRP that can be targeted to enhance cell migration and healing both in vitro and in vivo wound-healing models. Identifying other MRPs that are involved in cell migration and wound healing !can elucidate how these proteins function and how they affect cell motility. As a faster and acute alternative to genetically modified animal models, RNA interference (RNAi) can be easily used to deplete these targets directly at the wound sites by utilizing nanotechnology and other technologies to deliver and protect small interfering RNA (siRNA). CLINICAL RELEVANCEBoth chronic and acute wounds are costly and painful medical issues

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Stathmin Regulates Keratinocyte Proliferation and Migration during Cutaneous Regeneration

Cited by 14 publications

References 33 publications

Directed random walks and constraint programming reveal active pathways in hepatocyte growth factor signaling

Directed random walks and constraint programming reveal active pathways in hepatocyte growth factor signaling

An ELMO2-RhoG-ILK network modulates microtubule dynamics

Targeting Microtubules for Wound Repair

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