Alpha-actinin 4 and tumorigenesis of breast cancer

Abstract

Alpha-actinins (ACTNs) were originally identified as cytoskeletal proteins which cross-link filamentous actin to establish cytoskeletal architect that protects cells from mechanical stress and controls cell movement. Notably, unlike other ACTNs, alpha-actinin 4 (ACTN4) displays unique characteristics in signaling transduction, nuclear translocation, and gene expression regulation. Initial reports indicated that ACTN4 is part of the breast cancer cell motile apparatus and is highly expressed in the nucleus. These results imply that ACTN4 plays a role in breast cancer tumorigenesis. While several observations in breast cancer and other cancers support this hypothesis, little direct evidence links the tumorigenic phenotype with ACTN4-mediated pathological mechanisms. Recently, several studies have demonstrated that in addition to its role in coordinating cytoskeleton, ACTN4 interacts with signaling mediators, chromatin remodeling factors, and transcription factors including nuclear receptors. Thus, ACTN4 functions as a versatile promoter for breast cancer tumorigenesis and appears to be an ideal drug target for future therapeutic development.

Figure 13.1

(A) A schematic representation of the structural domains of ACTN. The N-terminal CH repeat constitutes a functional actin-binding domain (ABD), which can also bind to phosphoinositide and calcium. Following the ABD, four SRs form a rod-shaped structure that connects to the EF motif-integrated CaM-like domain. A list of ACTN binding partners is also shown under the corresponding domains. Among these binding partners, the proteins annotated in red are validated ACTN4 binding partners. Shown at the bottom are ACTN binding partners of which the interaction domains were not mapped. (B) A cartoon depicting a moving cell demonstrating the detailed localization of ACTN4 in stress fiber and adhesion sites. F-actin is shown in green and ACTN4 is shown as a brown line or a twisted cherry-like shape. Inside the cells, ACTN4 cross-links with F-actin to form stress fibers or locates in other motile apparatus components or in the nucleus. Close to the focal adhesion sites, ACTN4 directly links integrins with F-actin or other adhesion molecules, such as vinculin or talin.

Figure 13.2

A summary of key ACTN4-associated oncogenic pathways. In the nucleus, ACTN4 functions as a transcriptional coactivator to potentiate expression of nuclear receptor target genes, some of which promote cancer cell proliferation and survival. ACTN4 also interacts with NF-κB and chromatin remodeling factors, but the functional significance of these associations is currently not clear. In the cytosol, activated PI3K induces an association between ACTN4, Akt, and PIP3. Once anchored to PIP3, Akt is activated, thereby inhibiting apoptosis and promoting cell proliferation and migration. As a cytoskeletal protein, the interactions of ACTN4 and its cytoskeletal binding partners are subject to regulation by several signals. For example, loss of E-cadherin in colorectal cancer results in an increase in an ACTN4:β-catenin interaction which subsequently facilitates cytoskeletal reorganization and cancer cell migration. Similarly, disruption of the ACTN4:integrin or ACTN4:F-actin interactions results in acceleration of cytoskeletal reorganization and subsequent increases in cell migration.