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      Heat Shock Protein 27 Phosphorylation Regulates Tumor Cell Migration under Shear Stress

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          Abstract

          Heat shock protein 27 (HSP27) is a multifunctional protein that undergoes significant changes in its expression and phosphorylation in response to shear stress stimuli, suggesting that it may be involved in mechanotransduction. However, the mechanism of HSP27 affecting tumor cell migration under shear stress is still not clear. In this study, HSP27-enhanced cyan fluorescent protein (ECFP) and HSP27-Ypet plasmids are constructed to visualize the self-polymerization of HSP27 in living cells based on fluorescence resonance energy transfer technology. The results show that shear stress induces polar distribution of HSP27 to regulate the dynamic structure at the cell leading edge. Shear stress also promotes HSP27 depolymerization to small molecules and then regulates polar actin accumulation and focal adhesion kinase (FAK) polar activation, which further promotes tumor cell migration. This study suggests that HSP27 plays an important role in the regulation of shear stress-induced HeLa cell migration, and it also provides a theoretical basis for HSP27 as a potential drug target for metastasis.

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          Mechanical integration of actin and adhesion dynamics in cell migration.

          Margaret L. Gardel, Ian Schneider, Yvonne Aratyn-Schaus … (2010)
          Directed cell migration is a physical process that requires dramatic changes in cell shape and adhesion to the extracellular matrix. For efficient movement, these processes must be spatiotemporally coordinated. To a large degree, the morphological changes and physical forces that occur during migration are generated by a dynamic filamentous actin (F-actin) cytoskeleton. Adhesion is regulated by dynamic assemblies of structural and signaling proteins that couple the F-actin cytoskeleton to the extracellular matrix. Here, we review current knowledge of the dynamic organization of the F-actin cytoskeleton in cell migration and the regulation of focal adhesion assembly and disassembly with an emphasis on how mechanical and biochemical signaling between these two systems regulate the coordination of physical processes in cell migration.
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            Actin and alpha-actinin orchestrate the assembly and maturation of nascent adhesions in a myosin II motor-independent manner.

            Colin Choi, Miguel Vicente-Manzanares, Jessica Zareno … (2008)
            Using two-colour imaging and high resolution TIRF microscopy, we investigated the assembly and maturation of nascent adhesions in migrating cells. We show that nascent adhesions assemble and are stable within the lamellipodium. The assembly is independent of myosin II but its rate is proportional to the protrusion rate and requires actin polymerization. At the lamellipodium back, the nascent adhesions either disassemble or mature through growth and elongation. Maturation occurs along an alpha-actinin-actin template that elongates centripetally from nascent adhesions. Alpha-Actinin mediates the formation of the template and organization of adhesions associated with actin filaments, suggesting that actin crosslinking has a major role in this process. Adhesion maturation also requires myosin II. Rescue of a myosin IIA knockdown with an actin-bound but motor-inhibited mutant of myosin IIA shows that the actin crosslinking function of myosin II mediates initial adhesion maturation. From these studies, we have developed a model for adhesion assembly that clarifies the relative contributions of myosin II and actin polymerization and organization.
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              FAK signaling in human cancer as a target for therapeutics.

              Brian Y. Lee, Paul Timpson, Lisa Horvath … (2015)
              Focal adhesion kinase (FAK) is a key regulator of growth factor receptor- and integrin-mediated signals, governing fundamental processes in normal and cancer cells through its kinase activity and scaffolding function. Increased FAK expression and activity occurs in primary and metastatic cancers of many tissue origins, and is often associated with poor clinical outcome, highlighting FAK as a potential determinant of tumor development and metastasis. Indeed, data from cell culture and animal models of cancer provide strong lines of evidence that FAK promotes malignancy by regulating tumorigenic and metastatic potential through highly-coordinated signaling networks that orchestrate a diverse range of cellular processes, such as cell survival, proliferation, migration, invasion, epithelial-mesenchymal transition, angiogenesis and regulation of cancer stem cell activities. Such an integral role in governing malignant characteristics indicates that FAK represents a potential target for cancer therapeutics. While pharmacologic targeting of FAK scaffold function is still at an early stage of development, a number of small molecule-based FAK tyrosine kinase inhibitors are currently undergoing pre-clinical and clinical testing. In particular, PF-00562271, VS-4718 and VS-6063 show promising clinical activities in patients with selected solid cancers. Clinical testing of rationally designed FAK-targeting agents with implementation of predictive response biomarkers, such as merlin deficiency for VS-4718 in mesothelioma, may help improve clinical outcome for cancer patients. In this article, we have reviewed the current knowledge regarding FAK signaling in human cancer, and recent developments in the generation and clinical application of FAK-targeting pharmacologic agents.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Biomolecules
                Journal ID (iso-abbrev): Biomolecules
                Journal ID (publisher-id): biomolecules
                Title: Biomolecules
                Publisher: MDPI
                ISSN (Electronic): 2218-273X
                Publication date (Electronic): 30 January 2019
                Publication date Collection: February 2019
                Volume: 9
                Issue: 2
                Electronic Location Identifier: 50
                Affiliations
                [1 ]School of Biomedical Engineering, Dalian University of Technology, Liaoning IC Technology Key Lab, Dalian 116024, China; zbhwwj@ 123456mail.dlut.edu.cn (B.Z.); xfscjc@ 123456mail.dlut.edu.cn (F.X.); azizjatoi@ 123456hotmail.com (A.u.R.A.); shuai.shao_ss@ 123456foxmail.com (S.S.); lw@ 123456mail.dlut.edu.cn (W.L.); dengsha@ 123456mail.dlut.edu.cn (S.D.)
                [2 ]Institute of Biomedical Engineering, Chongqing University of Science and Technology, Chongqing 401331, China; zxc_228@ 123456163.com
                Author notes
                [* ]Correspondence: lbo@ 123456dlut.edu.cn ; Tel.: +86-411-84-706-002-3011
                Article
                Publisher ID: biomolecules-09-00050
                DOI: 10.3390/biom9020050
                PMC ID: 6406706
                PubMed ID: 30704117
                SO-VID: 250d8bda-acb7-48b2-920c-e65950842708
                Copyright © © 2019 by the authors.
                License:

                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
                Date received : 25 October 2018
                Date accepted : 25 January 2019
                Categories
                Subject: Article

                Keywords: heat shock protein 27,shear stress,migration,phosphorylation,signaling pathway
                Data availability:
                Keywords: heat shock protein 27, shear stress, migration, phosphorylation, signaling pathway

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