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      Proline-Rich Protein Tyrosine Kinase 2 in Inflammation and Cancer

      review-article
      1 , 2 , * , 1 , 1 , 1 , 3 , *
      Cancers
      MDPI
      FAK, Pyk2, inflammation, carcinogenesis, metastasis, EMT

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          Abstract

          Focal adhesion kinase (FAK) and its homologous FAK-related proline-rich tyrosine kinase 2 (Pyk2) contain the same domain, exhibit high sequence homology and are defined as a distinct family of non-receptor tyrosine kinases. This group of kinases plays critical roles in cytoskeletal dynamics and cell adhesion by regulating survival and growth signaling. This review summarizes the physiological and pathological functions of Pyk2 in inflammation and cancers. In particular, overexpression of Pyk2 in cancerous tissues is correlated with poor outcomes. Pyk2 stimulates multiple oncogenic signaling pathways, such as Wnt/β-catenin, PI3K/Akt, MAPK/ERK, and TGF-β/EGFR/VEGF, and facilitates carcinogenesis, migration, invasion, epithelial–mesenchymal transition and metastasis. Therefore, Pyk2 is a high-value therapeutic target and has clinical significance.

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          Most cited references84

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          Cellular functions of FAK kinases: insight into molecular mechanisms and novel functions.

          Focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2) are related tyrosine kinases that have important cellular functions, primarily through regulation of the cytoskeleton. Recent studies have identified multiple molecular mechanisms that regulate cytoskeletal responses, and have provided important and exciting insights into how FAK and Pyk2 control cellular processes such as cell migration. Equally exciting are reports of novel and originally unanticipated functions of these kinases, providing the groundwork for future avenues of investigation. This Commentary summarizes some of these recent discoveries that are relevant to the control of biological responses of the cell.
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            Focal adhesion kinase: a regulator of focal adhesion dynamics and cell movement.

            Engagement of integrin receptors with extracellular ligands gives rise to the formation of complex multiprotein structures that link the ECM to the cytoplasmic actin cytoskeleton. These adhesive complexes are dynamic, often heterogeneous structures, varying in size and organization. In motile cells, sites of adhesion within filopodia and lamellipodia are relatively small and transient and are referred to as 'focal complexes,' whereas adhesions underlying the body of the cell and localized to the ends of actin stress fibers are referred to as 'focal adhesions'. Signal transduction through focal complexes and focal adhesions has been implicated in the regulation of a number of key cellular processes, including growth factor induced mitogenic signals, cell survival and cell locomotion. The formation and remodeling of focal contacts is a dynamic process under the regulation of protein tyrosine kinases and small GTPases of the Rho family. In this review, we consider the role of the focal complex associated protein tyrosine kinase, Focal Adhesion Kinase (FAK), in the regulation of cell movement with the emphasis on how FAK regulates the flow of signals from the ECM to the actin cytoskeleton.
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              Antitumor activity and pharmacology of a selective focal adhesion kinase inhibitor, PF-562,271.

              Cancer cells are characterized by the ability to grow in an anchorage-independent manner. The activity of the nonreceptor tyrosine kinase, focal adhesion kinase (FAK), is thought to contribute to this phenotype. FAK localizes in focal adhesion plaques and has a role as a scaffolding and signaling protein for other adhesion molecules. Recent studies show a strong correlation between increased FAK expression and phosphorylation status and the invasive phenotype of aggressive human tumors. PF-562,271 is a potent, ATP-competitive, reversible inhibitor of FAK and Pyk2 catalytic activity with a IC(50) of 1.5 and 14 nmol/L, respectively. Additionally, PF-562,271 displayed robust inhibition in an inducible cell-based assay measuring phospho-FAK with an IC(50) of 5 nmol/L. PF-562,271 was evaluated against multiple kinases and displays >100x selectivity against a long list of nontarget kinases. PF-562,271 inhibits FAK phosphorylation in vivo in a dose-dependent fashion (calculated EC(50) of 93 ng/mL, total) after p.o. administration to tumor-bearing mice. In vivo inhibition of FAK phosphorylation (>50%) was sustained for >4 hours with a single p.o. dose of 33 mg/kg. Antitumor efficacy and regressions were observed in multiple human s.c. xenograft models. No weight loss, morbidity, or mortality were observed in any in vivo experiment. Tumor growth inhibition was dose and drug exposure dependent. Taken together, these data show that kinase inhibition with an ATP-competitive small molecule inhibitor of FAK decreases the phospho-status in vivo, resulting in robust antitumor activity.
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                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                08 May 2018
                May 2018
                : 10
                : 5
                : 139
                Affiliations
                [1 ]Institute of Precision Medicine, Jining Medical University, Jining 272067, China; baoyonghua2005@ 123456mail.jnmc.edu.cn (Y.B.); guoyongchen2005@ 123456mail.jnmc.edu.cn (Y.G.)
                [2 ]Department of Emergency Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
                [3 ]Department of Pathology, University of Illinois at Chicago, Chicago, IL 60612, USA
                Author notes
                [* ]Correspondence: xiangdon@ 123456uic.edu (X.Z.); wyang06@ 123456uic.edu (W.Y.); Tel.: +1-312-355-5915 (X.Z.); +86-537-361-6566 (W.Y.)
                Author information
                https://orcid.org/0000-0001-7437-9197
                Article
                cancers-10-00139
                10.3390/cancers10050139
                5977112
                29738483
                1c430fa9-82ee-46a3-a929-9683e10227ba
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 16 March 2018
                : 27 April 2018
                Categories
                Review

                fak,pyk2,inflammation,carcinogenesis,metastasis,emt
                fak, pyk2, inflammation, carcinogenesis, metastasis, emt

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