Ankrd2 in Mechanotransduction and Oxidative Stress Response in Skeletal Muscle: New Cues for the Pathogenesis of Muscular Laminopathies

Figures

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  Figure 1. Overview of Ankrd2 isoforms. (a) Schematic presentation of the Ankrd2 domain structure. (b) Alignment of protein sequences of Ankrd2 isoforms. Numbers correspond to amino acids. (c) Entries for five Ankrd2 isoforms reported in NCBI and Ensembl databases. ∗NCBI entries were updated in 2018.

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  Figure 2. Interaction network for Ankrd2. Interactors listed in Table 1 were loaded into the STRING database: https://string-db.org/. The majority of Ankrd2 interactors, including titin, telethonin, Ankrd1, Ankrd23, ZASP6, and calpain 3, are involved in mechanosignaling. Other Ankrd2 interacting proteins are involved in DNA binding and regulation of transcription and include p53, MECP2, ID3, YB-1, PAX6, PML, and NF-IL3. A-type lamins, including lamin A, its precursor prelamin A, and lamin C, are Ankrd2 interactors and are involved in multiple cellular functions, including modulation of the nuclear stiffness in response to mechanical and oxidative stress and of epigenetic factor activity. Ankrd2 also interacts with protein kinases, as Akt2, and with proteins with PDZ or SH3 domains able to mediate protein-protein interactions (including ZO-1 and β1-syntrophin, respectively). Note that the majority of Ankrd2 interactors were identified from in vitro studies or in nonmuscular cellular systems (see text and Table 1 for references).

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  Figure 3. Proposed pathogenic mechanisms in which Ankrd2 might be involved. In healthy muscle cells, physiological amounts of ROS or muscle differentiation induce Ankrd2 phosphorylation by Akt2 [15] and translocation into the nucleus, by binding to A-type lamins (black mesh) [98]. In the nucleus, Ankrd2 modulates the activation of muscle-specific and stress-responsive genes, by interacting with transcription factors (see text and Table 1 for references). In laminopathic muscle cells, mutated A-type lamins (red mesh) even in the absence of external stimuli recruit Ankrd2 into the nucleus. In addition to the already reported consequences, including an anomalous increase of ROS release, myogenic delay, and apoptotic cell death [98], potential pathogenic mechanisms, through which the altered nuclear localization of Ankrd2 might contribute to the pathogenesis of LMNA-related muscular disorders, are proposed.