Conditional ablation of p130Cas/BCAR1 adaptor protein impairs epidermal homeostasis by altering cell adhesion and differentiation

Leal, Maria del Pilar Camacho; Costamagna, Andrea; Tassone, Beatrice; Saoncella, Stefania; Simoni, Maria-Grazia De; Natalini, Dora; Dadone, Aurora; Sciortino, Marianna; Turco, Emilia; Defilippi, Paola; Calautti, Enzo; Cabodi, Sara

doi:10.1186/s12964-018-0289-z

Cited by 12 publications

(9 citation statements)

References 40 publications

(59 reference statements)

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“…Co-sedimentation and ELISA assays suggested a direct association of CSRP2 with F-actin 44 , 45 . Furthermore, CSRP2 could also sequester the scaffold protein p130Cas at focal adhesions, control lamellipodia formation, and reduce vascular smooth muscle cell motility 18 , 46 . These observations suggested that CSRP2 may be involved in the cytoskeletal regulation and cell motility, processes that are associated with cancer metastasis.…”

Section: Discussionmentioning

confidence: 99%

CSRP2 suppresses colorectal cancer progression via p130Cas/Rac1 axis-meditated ERK, PAK, and HIPPO signaling pathways

et al. 2020

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Metastasis is a major cause of death in patients with colorectal cancer (CRC). Cysteine-rich protein 2 (CSRP2) has been recently implicated in the progression and metastasis of a variety of cancers. However, the biological functions and underlying mechanisms of CSRP2 in the regulation of CRC progression are largely unknown. Methods: Immunohistochemistry, quantitative real-time polymerase chain reaction (qPCR) and Western blotting (WB) were used to detect the expression of CSRP2 in CRC tissues and paracancerous tissues. CSRP2 function in CRC was determined by a series of functional tests in vivo and in vitro . WB and immunofluorescence were used to determine the relation between CSRP2 and epithelial-mesenchymal transition (EMT). Co-immunoprecipitation and scanning electron microscopy were used to study the molecular mechanism of CSRP2 in CRC. Results: The CSRP2 expression level in CRC tissues was lower than in adjacent normal tissues and indicated poor prognosis in CRC patients. Functionally, CSRP2 could suppress the proliferation, migration, and invasion of CRC cells in vitro and inhibit CRC tumorigenesis and metastasis in vivo . Mechanistic investigations revealed a physical interaction between CSRP2 and p130Cas. CSRP2 could inhibit the activation of Rac1 by preventing the phosphorylation of p130Cas, thus activating the Hippo signaling pathway, and simultaneously inhibiting the ERK and PAK/LIMK/cortactin signaling pathways, thereby inhibiting the EMT and metastasis of CRC. Rescue experiments showed that blocking the p130Cas and Rac1 activation could inhibit EMT induced by CSRP2 silencing. Conclusion: Our results suggest that the CSRP2/p130Cas/Rac1 axis can inhibit CRC aggressiveness and metastasis through the Hippo, ERK, and PAK signaling pathways. Therefore, CSRP2 may be a potential therapeutic target for CRC.

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Section: Discussionmentioning

confidence: 99%

CSRP2 suppresses colorectal cancer progression via p130Cas/Rac1 axis-meditated ERK, PAK, and HIPPO signaling pathways

et al. 2020

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“…Notably, Bcar1 was one of the differentially methylated genes identified in the present study. Bcar1 is a vital scaffolding protein that modulates numerous essential cellular processes ( 62 , 63 ). It belongs to the Crk-associated substrate family of scaffolding proteins ( 64 ).…”

Section: Discussionmentioning

confidence: 99%

“…There is increasing evidence that Bcar1 serves a crucial role in cell-extracellular matrix adhesion, tissue homeostasis and pathogenesis of Kaposi's sarcoma-associated herpesvirus ( 65 ). Furthermore, the lack of Bcar1 in some cells may lead to altered integrin signaling, which is reflected by aberrant basal membrane adhesion ( 63 ). This is consistent with the expression of changes in core genes that affect adhesion in Schwann cells after PNI, as shown in the present study.…”

Section: Discussionmentioning

confidence: 99%

Identification of adhesion‑associated DNA methylation patterns in the peripheral nervous system

et al. 2020

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Schwann cells are unique glial cells in the peripheral nervous system. These cells provide a range of cytokines and nutritional factors to maintain axons and support axonal regeneration. However, little is known concerning adhesion-associated epigenetic changes that occur in Schwann cells after peripheral nerve injury (PNI). In the present study, adhesion-associated DNA methylation biomarkers were assessed between normal and injury peripheral nerve. Specifically, normal Schwann cells (NSCs) and activated Schwann cells (ASCs) were obtained from adult Wistar rats. After the Schwann cells were identified, proliferation and adhesion assays were used to assess differences between NSCs and ASCs. Methylated DNA immunoprecipitation-sequencing and bioinformatics analysis were used to identify and analyze the differentially methylated genes. Reverse transcription-quantitative PCR was performed to assess the expression levels of adhesion-associated genes. In the present study, the proliferation and adhesion assays demonstrated that ASCs had a more robust proliferative activity and adhesion compared with NSCs. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to identify methylation-associated biological processes and signaling pathways. Protein-protein interaction network analysis revealed that Fyn, Efna1, Jak2, Vav3, Flt4, Epha7, Crk, Kitlg, Ctnnb1 and Ptpn11 were potential markers for Schwann cell adhesion. The expression levels of several adhesion-associated genes, such as vinculin, BCAR1 scaffold protein, collagen type XVIII α1 chain and integrin subunit β6, in ASCs were altered compared with those in NSCs. The current study analyzed adhesion-associated DNA methylation patterns of Schwann cells and identified candidate genes that may potentially regulate Schwann cell adhesion in Wistar rats before and after PNI.

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“…This study focused on keratinocyte dysfunction in diabetic wounds, as keratinocytes are the main cell type found in the skin. The expression of PCNA was measured as a proliferation marker of keratinocytes [ 18 ], and expressions of TGM1 and LOR were measured as late differentiation markers of keratinocytes [ 19 ]. In addition, we chose HaCaT cells for our experiments because these cells have similar characteristics to epidermal stem cells [ 20 ] and are widely used in the study of the pathophysiology of diabetic foot ulcers [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

Inhibiting Hyper-O-GlcNAcylation of c-Myc accelerate diabetic wound healing by alleviating keratinocyte dysfunction

et al. 2021

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Background Diabetic foot ulcers characterized by delayed healing are one of the main complications of diabetes. Epidermal keratinocyte dysfunction has been found to play a pivotal role in the poor healing ability of diabetic wounds. In this study, we aimed to explore the relationship between c-Myc and its O-linked N-acetylglucosamine (O-GlcNAc) glycosylation (O-GlcNAcylation) modification and keratinocyte dysfunction in diabetic wounds. Methods Clinical wound samples were collected and a full-thickness skin defect wound model of diabetic rats was established. Re-epithelialization of wounds was observed by H&E staining and expressions of proliferating cell nuclear antigen, transglutaminase 1, loricrin, c-Myc and O-GlcNAc were measured by immunohistochemistry. The functional changes of proliferation, migration and differentiation of human immortalized epidermal cells (HaCaT) cells after overexpression or knockdown of c-Myc were observed. O-GlcNAcylation of c-Myc was confirmed using immunoprecipitation and proximity ligation assay. Stability of the c-Myc protein was measured using cycloheximide. Wound healing was observed after topical application of compounds that inhibited c-Myc or O-GlcNAc on diabetic wounds. Results Keratinocytes at the diabetic wound margin were characterized by active proliferation and division, slow migration and poor differentiation. Similar phenomena were observed in HaCaT cells cultured in 30 mM glucose and keratinocytes at the wound margin of the diabetic rats. The expression of c-Myc was increased in keratinocytes at the wound margin of diabetic rats, patients, and in HaCaT cells cultured with 30 mM glucose. Increased expression of c-Myc promoted the proliferation while inhibiting the migration and differentiation of the HaCaT cells, and inhibition of c-Myc promoted diabetic wound healing. Increased O-GlcNAcylation of c-Myc with 30 mM glucose stabilized the c-Myc proteins. Inhibition of O-GlcNAc ameliorated keratinocyte dysfunction and promoted diabetic wound healing. Conclusions Increased expression of c-Myc promoted abnormal proliferation and inhibited migration and differentiation of keratinocytes at the diabetic wound margin. Increased O-GlcNAcylation of c-Myc with 30 mM glucose stabilized the c-Myc proteins. Inhibition of c-Myc or O-GlcNAc alleviated delayed diabetic wound healing. These findings make c-Myc and O-GlcNAc potential therapeutic targets for diabetic wounds.

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Conditional ablation of p130Cas/BCAR1 adaptor protein impairs epidermal homeostasis by altering cell adhesion and differentiation

Cited by 12 publications

References 40 publications

CSRP2 suppresses colorectal cancer progression via p130Cas/Rac1 axis-meditated ERK, PAK, and HIPPO signaling pathways

CSRP2 suppresses colorectal cancer progression via p130Cas/Rac1 axis-meditated ERK, PAK, and HIPPO signaling pathways

Identification of adhesion‑associated DNA methylation patterns in the peripheral nervous system

Inhibiting Hyper-O-GlcNAcylation of c-Myc accelerate diabetic wound healing by alleviating keratinocyte dysfunction

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