ANKRD2

Ankyrin Repeat, PEST sequence and Proline-rich region (ARPP), also known as Ankyrin repeat domain-containing protein 2 is a is_associated_with::protein that in humans is encoded by the ANKRD2 is_associated_with::gene. ARPP is a member of the muscle ankyrin repeat proteins (MARP), which also includes CARP and DARP, and is highly expressed in cardiac and is_associated_with::skeletal muscle and in other tissues. Expression of AARP has been shown to be altered in patients with is_associated_with::dilated cardiomyopathy and is_associated_with::amyotrophic lateral sclerosis.

Structure
Two isoforms of ARPP have been documented; a 39.8 kDa is_associated_with::protein is_associated_with::isoform composed of 360 amino acids and a 36.2 kDa is_associated_with::protein is_associated_with::isoform composed of 327 amino acids. ANKRD2 has nine exons, four of which encode ankyrin repeats in the middle region of the is_associated_with::protein, a PEST-like and is_associated_with::Lysine-rich sequence in the N-terminal region, and a is_associated_with::Proline-rich sequence containing consensus sequences for is_associated_with::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 is_associated_with::intercalated discs; and expression in is_associated_with::brain, is_associated_with::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 is_associated_with::myocytes, however AARP is almost exclusively ventricular and only in adult is_associated_with::myocytes. AARP was also found to be expressed in is_associated_with::rhabdomyosarcomas, exhibiting a pattern distinct from is_associated_with::actin and is_associated_with::desmin.

Function
AARP localizes to both nuclei and is_associated_with::sarcomeres in muscle cells. ARPP may play a role in the differentiation of is_associated_with::myocytes, as ARPP expression was shown to be induced during the is_associated_with::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 is_associated_with::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 is_associated_with::titin at I-bands, which is potentiated by homo-dimerization and can alter the is_associated_with::protein kinase A/is_associated_with::protein kinase C is_associated_with::phosphorylation status of itself or is_associated_with::titin. These studies demonstrate a stretch-responsive relationship between AARP and is_associated_with::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), is_associated_with::skeletal muscles tended towards a more slower fiber type distribution, with longer resting is_associated_with::sarcomere length, decreased fiber stiffness, expression of a longer is_associated_with::titin isoform, greater degree of torque loss following is_associated_with::eccentric contraction-related injury, and enhanced expression of is_associated_with::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 is_associated_with::skeletal muscle. A study investigating AARP function in is_associated_with::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 is_associated_with::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 is_associated_with::skeletal muscle is_associated_with::denervation, persisting for four weeks following the insult. AARP (ANKRD2) gene expression was also shown to be rapidly induced in a model of is_associated_with::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 is_associated_with::muscular dystrophy with is_associated_with::myositis (mdm) caused by a small deletion in is_associated_with::titin, ANKRD2 is_associated_with::mRNA expression was shown to be significantly elevated in is_associated_with::skeletal muscle tissue along with that of CARP, suggesting a role for AARP in is_associated_with::titin-based signaling. Levels of AARP were also altered in a mouse model of diabetes.

Clinical Significance
In patients with is_associated_with::dilated cardiomyopathy, levels of AARP were upregulated.

AARP expression patterns have been shown to be altered in patients with is_associated_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 is_associated_with::oncocytoma and chromophobe renal cell carcinomas.

In non-pathologic physiology, AARP is_associated_with::mRNA expression in is_associated_with::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
 * is_associated_with::Titin
 * is_associated_with::YBX1,
 * TCAP,
 * PML and
 * is_associated_with::TP53.