ANKRD2

Structure

Two isoforms of ARPP have been documented; a 39.8 kDa protein isoform composed of 360 amino acids and a 36.2 kDa protein isoform composed of 327 amino acids. ANKRD2 has nine exons, four of which encode ankyrin repeats in the middle region of the protein, a PEST-like and Lysine-rich sequence in the N-terminal region, and a Proline-rich sequence containing consensus sequences for phosphorylation in the C-terminal region. It has been proposed that AARP can homo- or hetero-dimerize with other MARPs in an antiparallel fashion. ARPP is highly expressed in nuclei and I-bands in slow skeletal fibers and cardiac muscle, specifically in ventricular regions at intercalated discs; and expression in brain, pancreas and esophageal epithelium has also been documented. Though AARP and CARP proteins show significant homology, their expression profiles in muscle cells are markedly different; CARP is expressed throughout atria and ventricles, in development and in adult myocytes, however AARP is almost exclusively ventricular and only in adult myocytes. AARP was also found to be expressed in rhabdomyosarcomas, exhibiting a pattern distinct from actin and desmin.

Function

AARP localizes to both nuclei and sarcomeres in muscle cells. ARPP may play a role in the differentiation of myocytes, as ARPP expression was shown to be induced during the C2C12 differentiation in vitro. A role for AARP in regulating muscle gene expression and sensing stress signals was implicated in the finding that AARP colocalizes with the transcriptional co-activator and co-repressor PML in myoblast nuclei, and binds p53 to enhance the p21(WAFI/CIPI) promoter. It was further demonstrated that Nkx2.5 and p53 synergistically activate the ANKRD2 promoter to promote effects on myogenic differentiation. At the sarcomere, AARP binds titin at I-bands, which is potentiated by homo-dimerization and can alter the protein kinase A/protein kinase C phosphorylation status of itself or titin. These studies demonstrate a stretch-responsive relationship between AARP and Titin, which can be rapidly altered by post-translational mechanisms.

Functional insights into AARP function have come from transgenic studies. In mice lacking all three muscle ankyrin repeat proteins (MARPs), AARP, CARP, and DARP), skeletal muscles tended towards a more slower fiber type distribution, with longer resting sarcomere length, decreased fiber stiffness, expression of a longer titin isoform, greater degree of torque loss following eccentric contraction-related injury, and enhanced expression of MyoD and MLP. These findings suggest that AARP and related MARP proteins may play a role in the passive stiffness and gene regulatory roles in skeletal muscle. A study investigating AARP function in cardiac muscle in which AARP was knocked out alone or in combination with the other MARPs showed that mice displayed normal cardiac function at baseline and in response to pressure overload-induced cardiac hypertrophy, suggesting that these proteins are not essential for normal cardiac development or in response to a hypertrophic stimulus.

AARP has also shown to play a role in models of disease. AARP has also exhibited elevated expression following skeletal muscle denervation, persisting for four weeks following the insult. AARP (ANKRD2) gene expression was also shown to be rapidly induced in a model of eccentric contraction-related injury, showing peak expression (6-11 times normal value) within 12–24 hours following injury, suggesting that AARP may play a role in repair. In a mouse model of muscular dystrophy with myositis (mdm) caused by a small deletion in titin, ANKRD2 mRNA expression was shown to be significantly elevated in skeletal muscle tissue along with that of CARP, suggesting a role for AARP in titin-based signaling. Levels of AARP were also altered in a mouse model of diabetes.

Clinical Significance

In patients with dilated cardiomyopathy, levels of AARP were upregulated.

AARP expression patterns have been shown to be altered in patients with amyotrophic lateral sclerosis (ALS), with decreased expression in slow skeletal muscle fibers and increased expression in fast skeletal muscle fibers.

ARPP has also been shown to be a potentially useful biomarker for the differential diagnosis between oncocytoma and chromophobe renal cell carcinomas.

In non-pathologic physiology, AARP mRNA expression in skeletal muscle of patients was shown to be elevated two days following fatiguing jumping exercises. Levels of CARP, MLP and calpain-2 mRNA levels were also enhanced, suggesting that these molecules may be part of a signaling network activated by physical exercise.

Interactions

ANKRD2 has been shown to interact with