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FAK Signaling Pathway and Interaction Networks in Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 August 2020) | Viewed by 27765

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Special Issue Editors

Dr. Anna Alisi

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Guest Editor

Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy
Interests: liver diseases; non-alcoholic fatty liver disease; hepatocellular carcinoma; epigenetic mechanisms; microRNAs
Special Issues, Collections and Topics in MDPI journals

Dr. Rossella Rota

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Co-Guest Editor

Department of Oncohematology, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
Interests: Rhabdomyosarcoma; Pediatric soft tissue sarcomas; Epigenetics; Epigenetic drugs; Targeted therapy; Gene transcription; Chromatin modifiers; Diagnostic and prognostic
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase of 126 kDa, which localizes at sites of cell adhesion to the extracellular matrix (ECM) and mediates downstream events from integrins and other signals by acting as a signaling integrator. Therefore, FAK has been implicated in diverse signaling pathways and molecular networks that impact on cell growth, migration and survival, as well as, more recently, immune-escape of tumor cells through kinase-independent scaffolding functions. Moreover, FAK has multiple roles in the control of several process in human embryonic stem cells, such as in survival, proliferation, anchorage, contractility, and support or inhibition of self-renewal.

This multi-faced FAK roles indicate that this protein is a potential relevant pathogenic trigger in several complex diseases, mainly cancers, suggesting that FAK is a promising target for therapeutic use.

Along these lines, this Special Issue welcomes submissions of research articles and reviews covering molecular aspects of the FAK role in several diseases (cancer, cardiovascular and kidney diseases, etc.) and its interaction with other molecular networks and dynamic cell processes, such as cell differentiation and pluripotency, in both humans and experimental models. Pilot studies on the use of novel FAK inhibitors are also appreciated.

Dr. Anna Alisi
Dr. Rossella Rota
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Focal adhesion
Molecular interactions with extracellular signals
Signaling pathways
Nuclear interactors
Cancer development and progression
Cardiovascular disease pathogenesis
Epithelial to mesenchymal transition
Metastasis
Mutations and polymorphisms
Pharmacological and natural inhibitors

Published Papers (7 papers)

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Research

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17 pages, 2528 KiB

Open AccessArticle

A Lipidomic Signature Complements Stemness Features Acquisition in Liver Cancer Cells

by Irma Magaly Rivas Serna, Ilaria Romito, Andrea Maugeri, Oriana Lo Re, Sebastiano Giallongo, Gianluigi Mazzoccoli, Jude A. Oben, Giovanni Li Volti, Tommaso Mazza, Anna Alisi and Manlio Vinciguerra

Int. J. Mol. Sci. 2020, 21(22), 8452; https://doi.org/10.3390/ijms21228452 - 10 Nov 2020

Cited by 11 | Viewed by 3297

Abstract

Lipid catabolism and anabolism changes play a role in stemness acquisition by cancer cells, and cancer stem cells (CSCs) are particularly dependent on the activity of the enzymes involved in these processes. Lipidomic changes could play a role in CSCs’ ability to cause disease relapse and chemoresistance. The exploration of lipid composition and metabolism changes in CSCs in the context of hepatocellular cancer (HCC) is still incomplete and their lipidomic scenario continues to be elusive. We aimed to evaluate through high-throughput mass spectrometry (MS)-based lipidomics the levels of the members of the six major classes of sphingolipids and phospholipids in two HCC cell lines (HepG2 and Huh-7) silenced for the expression of histone variant macroH2A1 (favoring stemness acquisition), or silenced for the expression of focal adhesion tyrosine kinase (FAK) (hindering aggressiveness and stemness). Transcriptomic changes were evaluated by RNA sequencing as well. We found definite lipidomic and transcriptomic changes in the HCC lines upon knockdown (KD) of macroH2A1 or FAK, in line with the acquisition or loss of stemness features. In particular, macroH2A1 KD increased total sphingomyelin (SM) levels and decreased total lysophosphatidylcholine (LPC) levels, while FAK KD decreased total phosphatidylcholine (PC) levels. In conclusion, in HCC cell lines knocked down for specific signaling/epigenetic processes driving opposite stemness potential, we defined a lipidomic signature that hallmarks hepatic CSCs to be exploited for therapeutic strategies. Full article

(This article belongs to the Special Issue FAK Signaling Pathway and Interaction Networks in Diseases)

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13 pages, 5111 KiB

Open AccessArticle

Focal Adhesion Kinase (FAK) Over-Expression and Prognostic Implication in Pediatric Hepatocellular Carcinoma

by Paola Francalanci, Isabella Giovannoni, Cristiano De Stefanis, Ilaria Romito, Chiara Grimaldi, Aurora Castellano, Valentina D’Oria, Rita Alaggio and Anna Alisi

Int. J. Mol. Sci. 2020, 21(16), 5795; https://doi.org/10.3390/ijms21165795 - 12 Aug 2020

Cited by 12 | Viewed by 2498

Abstract

Focal adhesion kinase (FAK) is over-expressed and is correlated with aggressiveness in adult hepatocellular carcinoma (HCC). Inhibition of FAK decreases HCC invasiveness by down-regulating Enhancer of Zeste homolog 2 (EZH2), an epigenetic controller, that acts in transcriptional repression of a large number of genes via histone 3 methylation of lysine 27 (H3K27me3). Here, we investigated the hepatic expression of total FAK, EZH2, H3K27me3, and proliferating cell nuclear antigen (PCNA) in 17 pediatric HCCs and 8 healthy livers (CTRL). Quantitative imaging analysis showed that FAK gene/protein expression is up-regulated in HCCs compared to CTRL and, among tumor samples the levels of this gene/protein are significantly higher in cirrhotic HCCs than in a healthy milieu. Accordingly, the protein levels of EZH2 were also significantly increased in HCCs from a cirrhotic background. Intriguingly, the protein expression of FAK, EZH2, and PCNA significantly inversely correlated with tumor size. Finally, in HCC samples, mainly in cirrhotic background, the up-regulation of FAK gene positively correlated with that observed in β-Catenin gene. Conclusion: FAK gene/protein is over-expressed in pediatric HCCs concomitantly to EZH2 protein and β-Catenin gene, with a more significant up-regulation in a cirrhotic background. This triad of interactors deserves further investigations for translational application. Full article

(This article belongs to the Special Issue FAK Signaling Pathway and Interaction Networks in Diseases)

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20 pages, 2302 KiB

Open AccessArticle

Modulation of Calretinin Expression in Human Mesothelioma Cells Reveals the Implication of the FAK and Wnt Signaling Pathways in Conferring Chemoresistance towards Cisplatin

by Janine Wörthmüller, Valérie Salicio, Anne Oberson, Walter Blum and Beat Schwaller

Int. J. Mol. Sci. 2019, 20(21), 5391; https://doi.org/10.3390/ijms20215391 - 29 Oct 2019

Cited by 10 | Viewed by 3030

Abstract

Malignant mesothelioma (MM) is an aggressive asbestos-linked neoplasm, characterized by dysregulation of signaling pathways. Due to intrinsic or acquired chemoresistance, MM treatment options remain limited. Calretinin is a Ca²⁺-binding protein expressed during MM tumorigenesis that activates the FAK signaling pathway, promoting invasion and epithelial-to-mesenchymal transition. Constitutive calretinin downregulation decreases MM cells’ growth and survival, and impairs tumor formation in vivo. In order to evaluate early molecular events occurring during calretinin downregulation, we generated a tightly controlled IPTG-inducible expression system to modulate calretinin levels in vitro. Calretinin downregulation significantly reduced viability and proliferation of MM cells, attenuated FAK signaling and reduced the invasive phenotype of surviving cells. Importantly, surviving cells showed a higher resistance to cisplatin due to increased Wnt signaling. This resistance was abrogated by the Wnt signaling pathway inhibitor 3289-8625. In various MM cell lines and regardless of calretinin expression levels, blocking of FAK signaling activated the Wnt signaling pathway and vice versa. Thus, blocking both pathways had the strongest impact on MM cell proliferation and survival. Chemoresistance mechanisms in MM cells have resulted in a failure of single-agent therapies. Targeting of multiple components of key signaling pathways, including Wnt signaling, might be the future method-of-choice to treat MM. Full article

(This article belongs to the Special Issue FAK Signaling Pathway and Interaction Networks in Diseases)

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Graphical abstract

17 pages, 3276 KiB

Open AccessArticle

The Psoriasis Therapeutic Potential of a Novel Short Laminin Peptide C16

by Tsung-Chuan Ho, Shu-I Yeh, Show-Li Chen and Yeou-Ping Tsao

Int. J. Mol. Sci. 2019, 20(13), 3144; https://doi.org/10.3390/ijms20133144 - 27 Jun 2019

Cited by 7 | Viewed by 3370

Abstract

Psoriasis is a chronic inflammatory skin disease characterized by excessive growth of keratinocytes and hyperkeratosis in the epidermis. An abnormality of the non-lesional epidermis at an early stage of psoriasis is involved in triggering inflammatory cell infiltration into the dermis. Integrin α5β1 acts as a receptor for fibronectin and has been found to be overexpressed in non-lesional psoriatic epidermis. To investigate whether α5β1 integrin has a potential as a drug target for psoriasis treatment, the α5β1 integrin-binding peptide, C16, was used to obstruct the HaCat keratinocyte cellular responses induced by fibronectin (Fn) in culture and psoriasis-like skin inflammation induced in mice by imiquimod (IMQ). The C16 exhibited antagonistic activity against α5β1 integrin in HaCat cells, with evidence of suppression of the Fn-mediated proliferative, cytoskeletal, and inflammatory responses. Topical treatment with C16 greatly reduced the IMQ-induced epidermal hyperplasia, infiltration of neutrophils/macrophages, and expression of pro-inflammatory mediators in mouse skin. The C16SP (C16-derived short peptide; DITYVRLKF) also exhibited antagonistic activity, suppressing α5β1 integrin activity in culture, and reducing IMQ-induced skin inflammation. Taken together, this study provides the first evidence that α5β1 integrin may be a potential drug target for psoriasis. The synthetic C16 peptide may serve as an agent for psoriasis therapy. Full article

(This article belongs to the Special Issue FAK Signaling Pathway and Interaction Networks in Diseases)

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Review

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12 pages, 813 KiB

Open AccessReview

Involvement of the FAK Network in Pathologies Related to Altered Mechanotransduction

by Enrica Urciuoli and Barbara Peruzzi

Int. J. Mol. Sci. 2020, 21(24), 9426; https://doi.org/10.3390/ijms21249426 - 10 Dec 2020

Cited by 15 | Viewed by 3203

Abstract

Mechanotransduction is a physiological process in which external mechanical stimulations are perceived, interpreted, and translated by cells into biochemical signals. Mechanical stimulations exerted by extracellular matrix stiffness and cell–cell contacts are continuously applied to living cells, thus representing a key pivotal trigger for cell homeostasis, survival, and function, as well as an essential factor for proper organ development and metabolism. Indeed, a deregulation of the mechanotransduction process consequent to gene mutations or altered functions of proteins involved in perceiving cellular and extracellular mechanics can lead to a broad range of diseases, from muscular dystrophies and cardiomyopathies to cancer development and metastatization. Here, we recapitulate the involvement of focal adhesion kinase (FAK) in the cellular conditions deriving from altered mechanotransduction processes. Full article

(This article belongs to the Special Issue FAK Signaling Pathway and Interaction Networks in Diseases)

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23 pages, 757 KiB

Open AccessReview

The Crosstalk between FAK and Wnt Signaling Pathways in Cancer and Its Therapeutic Implication

by Janine Wörthmüller and Curzio Rüegg

Int. J. Mol. Sci. 2020, 21(23), 9107; https://doi.org/10.3390/ijms21239107 - 30 Nov 2020

Cited by 29 | Viewed by 7413

Abstract

Focal adhesion kinase (FAK) and Wnt signaling pathways are important contributors to tumorigenesis in several cancers. While most results come from studies investigating these pathways individually, there is increasing evidence of a functional crosstalk between both signaling pathways during development and tumor progression. A number of FAK–Wnt interactions are described, suggesting an intricate, context-specific, and cell type-dependent relationship. During development for instance, FAK acts mainly upstream of Wnt signaling; and although in intestinal homeostasis and mucosal regeneration Wnt seems to function upstream of FAK signaling, FAK activates the Wnt/β-catenin signaling pathway during APC-driven intestinal tumorigenesis. In breast, lung, and pancreatic cancers, FAK is reported to modulate the Wnt signaling pathway, while in prostate cancer, FAK is downstream of Wnt. In malignant mesothelioma, FAK and Wnt show an antagonistic relationship: Inhibiting FAK signaling activates the Wnt pathway and vice versa. As the identification of effective Wnt inhibitors to translate in the clinical setting remains an outstanding challenge, further understanding of the functional interaction between Wnt and FAK could reveal new therapeutic opportunities and approaches greatly needed in clinical oncology. In this review, we summarize some of the most relevant interactions between FAK and Wnt in different cancers, address the current landscape of Wnt- and FAK-targeted therapies in different clinical trials, and discuss the rationale for targeting the FAK–Wnt crosstalk, along with the possible translational implications. Full article

(This article belongs to the Special Issue FAK Signaling Pathway and Interaction Networks in Diseases)

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19 pages, 1890 KiB

Open AccessReview

FAK Signaling in Rhabdomyosarcoma

by Clara Perrone, Silvia Pomella, Matteo Cassandri, Maria Rita Braghini, Michele Pezzella, Franco Locatelli and Rossella Rota

Int. J. Mol. Sci. 2020, 21(22), 8422; https://doi.org/10.3390/ijms21228422 - 10 Nov 2020

Cited by 5 | Viewed by 4295

Abstract

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of children and adolescents. The fusion-positive (FP)-RMS variant expressing chimeric oncoproteins such as PAX3-FOXO1 and PAX7-FOXO1 is at high risk. The fusion negative subgroup, FN-RMS, has a good prognosis when non-metastatic. Despite a multimodal therapeutic approach, FP-RMS and metastatic FN-RMS often show a dismal prognosis with 5-year survival of less than 30%. Therefore, novel targets need to be discovered to develop therapies that halt tumor progression, reducing long-term side effects in young patients. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that regulates focal contacts at the cellular edges. It plays a role in cell motility, survival, and proliferation in response to integrin and growth factor receptors’ activation. FAK is often dysregulated in cancer, being upregulated and/or overactivated in several adult and pediatric tumor types. In RMS, both in vitro and preclinical studies point to a role of FAK in tumor cell motility/invasion and proliferation, which is inhibited by FAK inhibitors. In this review, we summarize the data on FAK expression and modulation in RMS. Moreover, we give an overview of the approaches to inhibit FAK in both preclinical and clinical cancer settings. Full article

(This article belongs to the Special Issue FAK Signaling Pathway and Interaction Networks in Diseases)

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