A Skin-depth Analysis of Integrins: Role of the Integrin Network in Health and Disease

Hegde, Samarth; Raghavan, Srikala

doi:10.3109/15419061.2013.854334

Cited by 39 publications

(30 citation statements)

References 120 publications

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“…Transcripts for genes encoding for protein phosphatases 37 and adhesion molecules, such as integrins and CAM 38, 39 (Figure 7a, lower heatmaps) were decreased in the absence of DLX3 and expression was not affected by PKC inhibition. Remarkably, the dual specificity phosphatases, which present downregulation during cSCC progression, 37 are downregulated in DLX3-null cells.…”

Section: Resultsmentioning

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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Section: Resultsmentioning

confidence: 99%

A novel DLX3–PKC integrated signaling network drives keratinocyte differentiation

et al. 2017

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“…Previous studies have revealed that miR-30a-5p acted as a tumor suppressor in multiple types of human neoplasms, including nonsmall cell lung cancer, 32 colorectal cancer, 33 hepatocellular cancer, 34 gastric cancer, 35 glioma, 36 and clear cell renal cell carcinoma. 12,13 Previous studies have identified that miR-30a-5p targets ITGB3 at the binding site, which is identical to the locus of LINC00461 interacting with miR-30a-5p. ITGB3, a member of integrin subfamily, is well known to be a key player in mediating cell adhesion and triggering intracellular signaling transduction.…”

Section: Discussionmentioning

confidence: 95%

“…12,13 Integrin β3 (ITGB3) is a member of the integrin subfamily and has been frequently reported to be implicated in multiple types of human neoplasms, including bladder cancer, 14 colorectal cancer, 15 salivary adenoid cystic carcinoma, 16 nonsmall cell lung cancer, 17,18 and hepatocellular carcinoma. 12,13 Integrin β3 (ITGB3) is a member of the integrin subfamily and has been frequently reported to be implicated in multiple types of human neoplasms, including bladder cancer, 14 colorectal cancer, 15 salivary adenoid cystic carcinoma, 16 nonsmall cell lung cancer, 17,18 and hepatocellular carcinoma.…”

Section: Introductionmentioning

confidence: 99%

LINC00461 promotes cell migration and invasion in breast cancer through miR‐30a‐5p/integrin β3 axis

Dong

Qian

Chen

et al. 2019

J of Cellular Biochemistry

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Mounting evidence has demonstrated that long noncoding RNAs (lncRNAs) are dysregulated and implicated in the occurrence and development of a wide range of human malignancies. LINC00461, a novel cancer‐related lncRNA, has been reported to be highly expressed and serve as oncogene in glioma; however, its biological role in breast cancer (BC) remains obscure. This study aimed to explore the role of LINC00461 in BC and elucidate the potential molecular mechanisms involved. In the current study, LINC00461 was found to be significantly upregulated in both BC tissues and cell lines. Besides, we found that high LINC00461 expression was associated with TNM stage and differentiation. Furthermore, functional studies demonstrated that LINC00461 expedited BC cell migration and invasion. Notably, LINC00461 was observed to enhance the expression of vimentin and zinc‐finger E‐box binding homeobox factor 1, suppress the expression of E‐cadherin, and promote the activation of extracellular signal‐regulated kinase and AKT signaling pathways. Mechanical investigations revealed that LINC00461 positively modulated integrin β3 (ITGB3) expression as miR‐30a‐5p sponge in BC cells. Taken together, LINC00461 exerts an oncogenic role in BC through miR‐30a‐5p/ITGB3 axis. Our data indicate that LINC00461 may be used to be a novel candidate therapeutic target and a valuable diagnostic biomarker for BC.

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“…The sequence composition of domain 17 resembles that seen in other tropoelastin domains such as domains 15 and 19. We aim to explore the 24…”

Section: Discussionmentioning

confidence: 99%

“…Integrins influence cellular morphology, and facilitate processes such as cell migration and proliferation, wound repair, tissue organization, development, and host immune responses [24][25][26]. Integrins also participate in the pathogenesis of a wide range of diseases such as arthritis, cardiovascular disease, inflammation, microbial and parasitic infection, cancer, and glaucoma [27][28][29][30].…”

Section: Introductionmentioning

confidence: 99%

A cell adhesive peptide from tropoelastin promotes sequential cell attachment and spreading via distinct receptors

2017

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Tropoelastin is the dominant monomer that assembles to form elastin, which confers elasticity to vertebrate elastic tissues including skin, arteries, and lungs. Tropoelastin interacts with cells through cell surface receptors including integrins and glycosaminoglycans (GAGs). As the region 17-18 is recognized as a key region in cell attachment and spreading, we utilized C-terminal truncated tropoelastin constructs containing dissected sections of domain 18. We mapped a cell-interactive sequence of tropoelastin to domain 17 and the first six amino acids (aa) of domain 18. Further delineation identified a 21-residue sequence (Peptide 302-322) which promoted cell attachment and spreading indistinguishable from that to N18, a construct encompassing the full domains 17-18. Alanine substitution of the lysines at positions 11 and 14 in Peptide 302-322 effectively abolished cell binding. This reliance on lysines pointed to a role for GAGs, which was assessed by heparan sulfate inhibition, leading to 85.9 ± 4.2% decreased cell binding, while inhibition of integrins using ethylenediaminetetraacetic acid did not affect attachment. In contrast, selective antibody blocking of the integrin α family prevented cell spreading by 92.5 ± 8.9%. We propose a two-step mechanism by which cell interactions occur at this central region of tropoelastin: initially, cell adhesion is mediated by GAGs, which contact the lysine residues within the target sequence, and subsequently facilitate cell spreading modulated by integrins, specifically α β and α β . We conclude that this region comprises a tropoelastin-derived, cell-interactive sequence that independently mediates potent cell binding and spreading via sequential recognition of GAG and integrin cell surface receptors.

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A Skin-depth Analysis of Integrins: Role of the Integrin Network in Health and Disease

Cited by 39 publications

References 120 publications

A novel DLX3–PKC integrated signaling network drives keratinocyte differentiation

A novel DLX3–PKC integrated signaling network drives keratinocyte differentiation

LINC00461 promotes cell migration and invasion in breast cancer through miR‐30a‐5p/integrin β3 axis

A cell adhesive peptide from tropoelastin promotes sequential cell attachment and spreading via distinct receptors

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