Integrin-Linked Kinase Is Indispensable for Keratinocyte Differentiation and Epidermal Barrier Function

Sayedyahossein, Samar; Rudkouskaya, Alena; Leclerc, Valerie; Dagnino, Lina

doi:10.1016/j.jid.2015.10.056

Cited by 16 publications

(12 citation statements)

References 36 publications

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“…Given that ILK-deficient keratinocytes exhibit severely impaired internalization of these bacteria, a major component of the increased invasion observed is likely associated with the loss of the paracellular permeability barrier in these animals. 102 Significantly, ILKdeficient epidermis also exhibits upregulation of antimicrobial peptides, such as psoriasin, 140 in agreement with the known cutaneous responses to its increased susceptibility to infection.…”

Section: Infectionsupporting

confidence: 58%

“…101 In the absence of ILK, signaling through CaSR is altered and RhoA activation is impaired in cultured keratinocytes. 102 Under these conditions, Ecadherin, and ZO-1 fail to translocate to the cell membrane, through mechanisms that involve impaired RhoA activation and endosomal delivery of junction proteins to the plasma membrane. 103 As a result, adherens and tight junctions fail to form.…”

Section: Integrin-linked Kinasementioning

confidence: 99%

“…These abnormalities are also associated with increased permeability to medium molecular-weight tracers, indicating impairment of paracellular tight-junction barrier properties toward macromolecules. 102…”

Section: Integrin-linked Kinasementioning

confidence: 99%

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Scaffolding proteins in the development and maintenance of the epidermal permeability barrier

Crawford

Dagnino

2017

Tissue Barriers

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The skin of mammals and other terrestrial vertebrates protects the organism against the external environment, preventing heat, water and electrolyte loss, as well as entry of chemicals and pathogens. Impairments in the epidermal permeability barrier function are associated with the genesis and/or progression of a variety of pathological conditions, including genetic inflammatory diseases, microbial and viral infections, and photodamage induced by UV radiation. In mammals, the outside-in epidermal permeability barrier is provided by the joint action of the outermost cornified layer, together with assembled tight junctions in granular keratinocytes found in the layers underneath. Tight junctions serve as both outside-in and inside-out barriers, and impede paracellular movements of ions, water, macromolecules and microorganisms. At the molecular level, tight junctions consist of integral membrane proteins that form an extracellular seal between adjacent cells, and associate with cytoplasmic scaffold proteins that serve as links with the actin cytoskeleton. In this review, we address the roles that scaffold proteins play specifically in the establishment and maintenance of the epidermal permeability barrier, and how various pathologies alter or impair their functions.

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Section: Infectionsupporting

confidence: 58%

Section: Integrin-linked Kinasementioning

confidence: 99%

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Scaffolding proteins in the development and maintenance of the epidermal permeability barrier

Crawford

Dagnino

2017

Tissue Barriers

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“…Other signaling pathways have been determined to be indispensable for keratinocyte differentiation and barrier function. 53, 54 It remains to be determined which other DLX3-dependent signaling pathway will prove to be essential in epidermal homeostasis. Taken together, the work presented here reveals a DLX3–PKC axis in the regulation of keratinocyte proliferation and differentiation balance.…”

Section: Discussionmentioning

confidence: 99%

A novel DLX3–PKC integrated signaling network drives keratinocyte differentiation

et al. 2017

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Epidermal homeostasis relies on a well-defined transcriptional control of keratinocyte proliferation and differentiation, which is critical to prevent skin diseases such as atopic dermatitis, psoriasis or cancer. We have recently shown that the homeobox transcription factor DLX3 and the tumor suppressor p53 co-regulate cell cycle-related signaling and that this mechanism is functionally involved in cutaneous squamous cell carcinoma development. Here we show that DLX3 expression and its downstream signaling depend on protein kinase C α (PKCα) activity in skin. We found that following 12-O-tetradecanoyl-phorbol-13-acetate (TPA) topical treatment, DLX3 expression is significantly upregulated in the epidermis and keratinocytes from mice overexpressing PKCα by transgenic targeting (K5-PKCα), resulting in cell cycle block and terminal differentiation. Epidermis lacking DLX3 (DLX3cKO), which is linked to the development of a DLX3-dependent epidermal hyperplasia with hyperkeratosis and dermal leukocyte recruitment, displays enhanced PKCα activation, suggesting a feedback regulation of DLX3 and PKCα. Of particular significance, transcriptional activation of epidermal barrier, antimicrobial peptide and cytokine genes is significantly increased in DLX3cKO skin and further increased by TPA-dependent PKC activation. Furthermore, when inhibiting PKC activity, we show that epidermal thickness, keratinocyte proliferation and inflammatory cell infiltration are reduced and the PKC-DLX3-dependent gene expression signature is normalized. Independently of PKC, DLX3 expression specifically modulates regulatory networks such as Wnt signaling, phosphatase activity and cell adhesion. Chromatin immunoprecipitation sequencing analysis of primary suprabasal keratinocytes showed binding of DLX3 to the proximal promoter regions of genes associated with cell cycle regulation, and of structural proteins and transcription factors involved in epidermal differentiation. These results indicate that Dlx3 potentially regulates a set of crucial genes necessary during the epidermal differentiation process. Altogether, we demonstrate the existence of a robust DLX3-PKCα signaling pathway in keratinocytes that is crucial to epidermal differentiation control and cutaneous homeostasis.

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“…The absence of ILK in epidermal cells led to defective cell differentiation and aberrant translocation of the CaSR calcium-sensing receptor (Sayedyahossein et al, 2016). In plants, CML9, a Ca 2+ sensor, and negative PTI modulator interacted with ILK1 in vivo and inhibited ILK1 kinase activity (Brauer et al, 2016), suggesting that ILK1-CML9 are part of a putative pathway mediated by pathogen-triggered Ca 2+ waves.…”

Section: Regulation Of Ilksmentioning

confidence: 99%

Insights into the Structure, Function, and Ion-Mediated Signaling Pathways Transduced by Plant Integrin-Linked Kinases

et al. 2017

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Kinases facilitate detection of extracellular signals and set in motion cellular responses for plant adaptation and survival. Some of the energy utilized for kinase signal processing is produced through the activity of ion transporters. Additionally, the synergy between cellular ions and signal transduction influences plant response to pathogens, and their growth and development. In plants, the signaling elements that connect cell wall and membrane sensors with ion homeostasis and transport-mediated processes are largely unknown. Current research indicates that plant Integrin-Linked Kinases (ILKs), a subfamily Raf-like MAP2K Kinases, may have evolved to fulfill this role. In this review, we explore new findings on plant ILKs placing a particular focus on the connection between ILKs proteins unique structural features and ILKs functions. The ankyrin repeat motifs and the kinase domains of ILKs in Arabidopsis and land plants lineage, respectively, are analyzed and discussed as potential determinants of ILKs’ metal ion cofactor specificity and their enzymatic and interaction activities. Further, ILKs regulation through gene expression, subcellular localization, and ions and ion transporters is reviewed in the context of recent studies. Finally, using evidence from literature and interactomics databanks, we infer ILKs-dependent cellular pathways and highlight their potential in transmitting multiple types of signals originating at the interface between the cell wall and plasma membrane.

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Integrin-Linked Kinase Is Indispensable for Keratinocyte Differentiation and Epidermal Barrier Function

Cited by 16 publications

References 36 publications

Scaffolding proteins in the development and maintenance of the epidermal permeability barrier

Scaffolding proteins in the development and maintenance of the epidermal permeability barrier

A novel DLX3–PKC integrated signaling network drives keratinocyte differentiation

Insights into the Structure, Function, and Ion-Mediated Signaling Pathways Transduced by Plant Integrin-Linked Kinases

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