The Fifth Sense: Mechanosensory Regulation of Alpha-actinin-4 and Its Relevance for Cancer Metastasis

Overview

Journal Semin Cell Dev Biol

Specialties Cell Biology
Reproductive Medicine

Date 2017 Jun 6

PMID 28579451

Citations 18

Authors

Dustin G Thomas

Douglas N Robinson

Affiliations

Soon will be listed here.

Abstract

Metastatic cancer cells invading through dense tumor stroma experience internal and external forces that are sensed through a variety of mechanosensory proteins that drive adaptations for specific environments. Alpha-actinin-4 (ACTN4) is a member of the α-actinin family of actin crosslinking proteins that is upregulated in several types of cancers. It shares 86% protein similarity with α-actinin-1, another non-muscle ACTN isoform, which appears to have a more modest role, if any, in cancer progression. While they share regulatory mechanisms, such as phosphorylation, calcium binding, phosphatidyl inositol binding, and calpain cleavage, α-actinin-4 exhibits a unique mechanosensory regulation that α-actinin-1 does not. This behavior is mediated, at least in part, by each protein's actin-binding affinity as well as the catch-slip-bond behavior of the actin binding domains. We will discuss currently known modes of ACTN4 regulation, their interactions, and how mechanosensation may provide major therapeutic targeting potential for cancer metastasis.

Citing Articles

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References

Discher D, Janmey P, Wang Y . Tissue cells feel and respond to the stiffness of their substrate. Science. 2005; 310(5751):1139-43. DOI: 10.1126/science.1116995. View

Sahai E, Marshall C . Differing modes of tumour cell invasion have distinct requirements for Rho/ROCK signalling and extracellular proteolysis. Nat Cell Biol. 2003; 5(8):711-9. DOI: 10.1038/ncb1019. View

Schiffhauer E, Luo T, Mohan K, Srivastava V, Qian X, Griffis E . Mechanoaccumulative Elements of the Mammalian Actin Cytoskeleton. Curr Biol. 2016; 26(11):1473-1479. PMC: 4899209. DOI: 10.1016/j.cub.2016.04.007. View

Shao H, Wang J, Pollak M, Wells A . α-actinin-4 is essential for maintaining the spreading, motility and contractility of fibroblasts. PLoS One. 2010; 5(11):e13921. PMC: 2978680. DOI: 10.1371/journal.pone.0013921. View

Friedl P, Noble P, Shields E, Zanker K . Locomotor phenotypes of unstimulated CD45RAhigh and CD45ROhigh CD4+ and CD8+ lymphocytes in three-dimensional collagen lattices. Immunology. 1994; 82(4):617-24. PMC: 1414901. View

Roca-Cusachs P, del Rio A, Puklin-Faucher E, Gauthier N, Biais N, Sheetz M . Integrin-dependent force transmission to the extracellular matrix by α-actinin triggers adhesion maturation. Proc Natl Acad Sci U S A. 2013; 110(15):E1361-70. PMC: 3625291. DOI: 10.1073/pnas.1220723110. View

Jackson W, Jaasma M, Baik A, Keaveny T . Over-expression of alpha-actinin with a GFP fusion protein is sufficient to increase whole-cell stiffness in human osteoblasts. Ann Biomed Eng. 2008; 36(10):1605-14. DOI: 10.1007/s10439-008-9533-9. View

Dourdin N, Bhatt A, Dutt P, Greer P, Arthur J, Elce J . Reduced cell migration and disruption of the actin cytoskeleton in calpain-deficient embryonic fibroblasts. J Biol Chem. 2001; 276(51):48382-8. DOI: 10.1074/jbc.M108893200. View

Meacci G, Wolfenson H, Liu S, Stachowiak M, Iskratsch T, Mathur A . α-Actinin links extracellular matrix rigidity-sensing contractile units with periodic cell-edge retractions. Mol Biol Cell. 2016; 27(22):3471-3479. PMC: 5221581. DOI: 10.1091/mbc.E16-02-0107. View

10.

Armstrong T, Packham G, Murphy L, Bateman A, Conti J, Fine D . Type I collagen promotes the malignant phenotype of pancreatic ductal adenocarcinoma. Clin Cancer Res. 2004; 10(21):7427-37. DOI: 10.1158/1078-0432.CCR-03-0825. View

11.

Franco O, Shaw A, Strand D, Hayward S . Cancer associated fibroblasts in cancer pathogenesis. Semin Cell Dev Biol. 2009; 21(1):33-9. PMC: 2823834. DOI: 10.1016/j.semcdb.2009.10.010. View

12.

Honda K . The biological role of actinin-4 (ACTN4) in malignant phenotypes of cancer. Cell Biosci. 2015; 5:41. PMC: 4539665. DOI: 10.1186/s13578-015-0031-0. View

13.

Bisi S, Disanza A, Malinverno C, Frittoli E, Palamidessi A, Scita G . Membrane and actin dynamics interplay at lamellipodia leading edge. Curr Opin Cell Biol. 2013; 25(5):565-73. DOI: 10.1016/j.ceb.2013.04.001. View

14.

Izaguirre G, Aguirre L, Hu Y, Lee H, Schlaepfer D, Aneskievich B . The cytoskeletal/non-muscle isoform of alpha-actinin is phosphorylated on its actin-binding domain by the focal adhesion kinase. J Biol Chem. 2001; 276(31):28676-85. DOI: 10.1074/jbc.M101678200. View

15.

Mahadevan D, Von Hoff D . Tumor-stroma interactions in pancreatic ductal adenocarcinoma. Mol Cancer Ther. 2007; 6(4):1186-97. DOI: 10.1158/1535-7163.MCT-06-0686. View

16.

Provenzano P, Cuevas C, Chang A, Goel V, Von Hoff D, Hingorani S . Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell. 2012; 21(3):418-29. PMC: 3371414. DOI: 10.1016/j.ccr.2012.01.007. View

17.

Goldmann W, Isenberg G . Analysis of filamin and alpha-actinin binding to actin by the stopped flow method. FEBS Lett. 1993; 336(3):408-10. DOI: 10.1016/0014-5793(93)80847-n. View

18.

Fukumoto M, Kurisu S, Yamada T, Takenawa T . α-Actinin-4 enhances colorectal cancer cell invasion by suppressing focal adhesion maturation. PLoS One. 2015; 10(4):e0120616. PMC: 4393021. DOI: 10.1371/journal.pone.0120616. View

19.

Koser D, Thompson A, Foster S, Dwivedy A, Pillai E, Sheridan G . Mechanosensing is critical for axon growth in the developing brain. Nat Neurosci. 2016; 19(12):1592-1598. PMC: 5531257. DOI: 10.1038/nn.4394. View

20.

Yamamoto S, Tsuda H, Honda K, Kita T, Takano M, Tamai S . Actinin-4 expression in ovarian cancer: a novel prognostic indicator independent of clinical stage and histological type. Mod Pathol. 2007; 20(12):1278-85. DOI: 10.1038/modpathol.3800966. View