Abstract
BackgroundAnkrd2 (also known as Arpp) together with Ankrd1/CARP and DARP are members of the MARP mechanosensing proteins that form a complex with titin (N2A)/calpain 3 protease/myopalladin. In muscle, Ankrd2 is located in the I-band of the sarcomere and moves to the nucleus of adjacent myofibers on muscle injury. In myoblasts it is predominantly in the nucleus and on differentiation shifts from the nucleus to the cytoplasm. In agreement with its role as a sensor it interacts both with sarcomeric proteins and transcription factors.Methodology/Principal FindingsExpression profiling of endogenous Ankrd2 silenced in human myotubes was undertaken to elucidate its role as an intermediary in cell signaling pathways. Silencing Ankrd2 expression altered the expression of genes involved in both intercellular communication (cytokine-cytokine receptor interaction, endocytosis, focal adhesion, tight junction, gap junction and regulation of the actin cytoskeleton) and intracellular communication (calcium, insulin, MAPK, p53, TGF-β and Wnt signaling). The significance of Ankrd2 in cell signaling was strengthened by the fact that we were able to show for the first time that Nkx2.5 and p53 are upstream effectors of the Ankrd2 gene and that Ankrd1/CARP, another MARP member, can modulate the transcriptional ability of MyoD on the Ankrd2 promoter. Another novel finding was the interaction between Ankrd2 and proteins with PDZ and SH3 domains, further supporting its role in signaling. It is noteworthy that we demonstrated that transcription factors PAX6, LHX2, NFIL3 and MECP2, were able to bind both the Ankrd2 protein and its promoter indicating the presence of a regulatory feedback loop mechanism.Conclusions/SignificanceIn conclusion we demonstrate that Ankrd2 is a potent regulator in muscle cells affecting a multitude of pathways and processes.
Highlights
For any cell it is important to respond to external stimuli as quickly and efficiently as possible, this is especially true for striated muscle cells that are subjected to a variety of stress on a continuous basis
The muscle ankyrin repeat proteins (MARPs) family of proteins is composed of Ankrd1/CARP [3,4,5], Ankrd2 [6,7] known as ARPP [8] and DARP [9]
To identify the Ankrd2 related genes involved in the crucial steps of the myogenic program a series of DNA microarray experiments were performed using total RNA from silenced and non-silenced human skeletal muscle cells (CHQ5B)
Summary
For any cell it is important to respond to external stimuli as quickly and efficiently as possible, this is especially true for striated muscle cells that are subjected to a variety of stress on a continuous basis. A signal complex sensitive to mechanical stress (such as stretch and muscle injury) is located at the I-band of the sarcomere and assembled on the N2A region of titin. Titin serves as a scaffold for the organization of the signal complex composed of myopalladin, calpain 3 and the muscle ankyrin repeat proteins (MARPs) [1,2]. The MARP family of proteins is composed of Ankrd1/CARP [3,4,5], Ankrd2 [6,7] known as ARPP [8] and DARP [9]. Ankrd ( known as Arpp) together with Ankrd1/CARP and DARP are members of the MARP mechanosensing proteins that form a complex with titin (N2A)/calpain 3 protease/myopalladin. Ankrd is located in the I-band of the sarcomere and moves to the nucleus of adjacent myofibers on muscle injury. In agreement with its role as a sensor it interacts both with sarcomeric proteins and transcription factors
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