Ankyrin Repeat, PEST sequence and Proline-rich region (ARPP), also known as Ankyrin repeat domain-containing protein 2 is a
protein that in humans is encoded by the ANKRD2gene.[5][6][7][8] ARPP is a member of the muscle ankyrin repeat proteins (MARP), which also includes
CARP and
DARP, and is highly expressed in
cardiac and
skeletal muscle and in other tissues. Expression of ARPP has been shown to be altered in patients with
dilated cardiomyopathy and
amyotrophic lateral sclerosis.
A role for Ankrd2 in tumor progression and metastases spreading has also been described.[9][10]
Structure
Two isoforms of ARPP have been documented; a 39.8 kDa
proteinisoform composed of 360 amino acids[11] and a 36.2 kDa
proteinisoform composed of 327 amino acids.[12]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.[13][14] It has been proposed that ARPP can homo- or hetero-dimerize with other MARPs in an antiparallel fashion.[15] ARPP is highly expressed in
nuclei and
I-bands in slow skeletal fibers[13][16] and cardiac muscle, specifically in
ventricular regions[14] at
intercalated discs;[17] and expression in
brain,
pancreas and
esophageal epithelium has also been documented.[16][18] Though ARPP 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 ARPP is almost exclusively
ventricular and only in adult
myocytes. ARPP was also found to be expressed in
rhabdomyosarcomas, exhibiting a pattern distinct from
actin and
desmin.[19]
Function
ARPP 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.[19] A role for ARPP in regulating muscle gene expression and sensing stress signals was implicated in the finding that ARPP colocalizes with the transcriptional co-activator and co-repressor
PML in
myoblastnuclei, and binds
p53 to enhance the p21(WAFI/CIPI) promoter.[20] It was further demonstrated that Nkx2.5 and
p53 synergistically activate the ANKRD2 promoter to promote effects on myogenic differentiation.[21] At the sarcomere, ARPP binds
titin at
I-bands, which is potentiated by homo-dimerization and can alter the
protein kinase A/
protein kinase Cphosphorylation status of itself or
titin.[15] These studies demonstrate a stretch-responsive relationship between ARPP and
Titin, which can be rapidly altered by post-translational mechanisms.
Functional insights into ARPP function have come from transgenic studies. In mice lacking all three muscle ankyrin repeat proteins (MARPs), ARPP,
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 ARPP and related MARP proteins may play a role in the passive stiffness and gene regulatory roles in
skeletal muscle.[22] A study investigating ARPP function in
cardiac muscle in which ARPP 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.[23]
ARPP has also shown to play a role in models of disease. ARPP has also exhibited elevated expression following
skeletal muscledenervation, persisting for four weeks following the insult.[16] ARPP (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 ARPP may play a role in repair.[24] In a mouse model of
muscular dystrophy with
myositis (mdm) caused by a small deletion in
titin, ANKRD2mRNA expression was shown to be significantly elevated in
skeletal muscle tissue along with that of
CARP, suggesting a role for ARPP in
titin-based signaling.[25] Levels of ARPP were also altered in a mouse model of diabetes.[26]
In non-pathologic physiology, ARPP
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.[30]
Ankrd2 has been shown to be involved in the progression of some types of cancers, such as osteosarcoma[9] and head and neck squamous cell carcinoma.[10]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Kemp TJ, Sadusky TJ, Saltisi F, Carey N, Moss J, Yang SY, Sassoon DA, Goldspink G, Coulton GR (Sep 2000). "Identification of Ankrd2, a novel skeletal muscle gene coding for a stretch-responsive ankyrin-repeat protein". Genomics. 66 (3): 229–41.
doi:
10.1006/geno.2000.6213.
PMID10873377.
^
abcdeKojic S, Medeot E, Guccione E, Krmac H, Zara I, Martinelli V, Valle G, Faulkner G (May 2004). "The Ankrd2 protein, a link between the sarcomere and the nucleus in skeletal muscle". J. Mol. Biol. 339 (2): 313–25.
doi:
10.1016/j.jmb.2004.03.071.
PMID15136035.
^Mckoy G, Hou Y, Yang SY, Vega Avelaira D, Degens H, Goldspink G, Coulton GR (May 2005). "Expression of Ankrd2 in fast and slow muscles and its response to stretch are consistent with a role in slow muscle function". J. Appl. Physiol. 98 (6): 2337–43, discussion 2320.
doi:
10.1152/japplphysiol.01046.2004.
PMID15677738.
S2CID17104014.
^
abPallavicini A, Kojić S, Bean C, Vainzof M, Salamon M, Ievolella C, Bortoletto G, Pacchioni B, Zatz M, Lanfranchi G, Faulkner G, Valle G (Jul 2001). "Characterization of human skeletal muscle Ankrd2". Biochemical and Biophysical Research Communications. 285 (2): 378–86.
doi:
10.1006/bbrc.2001.5131.
PMID11444853.
^
abMoriyama M, Tsukamoto Y, Fujiwara M, Kondo G, Nakada C, Baba T, Ishiguro N, Miyazaki A, Nakamura K, Hori N, Sato K, Shomori K, Takeuchi K, Satoh H, Mori S, Ito H (Jul 2001). "Identification of a novel human ankyrin-repeated protein homologous to CARP". Biochemical and Biophysical Research Communications. 285 (3): 715–23.
doi:
10.1006/bbrc.2001.5216.
PMID11453652.
^Jasnic-Savovic J, Nestorovic A, Savic S, Karasek S, Vitulo N, Valle G, Faulkner G, Radojkovic D, Kojic S (Jun 2015). "Profiling of skeletal muscle Ankrd2 protein in human cardiac tissue and neonatal rat cardiomyocytes". Histochemistry and Cell Biology. 143 (6): 583–97.
doi:
10.1007/s00418-015-1307-5.
PMID25585647.
S2CID5174178.
^Wang L, Lei M, Xiong Y (Apr 2011). "Molecular characterization and different expression patterns of the muscle ankyrin repeat protein (MARP) family during porcine skeletal muscle development in vitro and in vivo". Animal Biotechnology. 22 (2): 87–99.
doi:
10.1080/10495398.2011.559562.
PMID21500110.
S2CID26069450.
^Kojic S, Medeot E, Guccione E, Krmac H, Zara I, Martinelli V, Valle G, Faulkner G (May 2004). "The Ankrd2 protein, a link between the sarcomere and the nucleus in skeletal muscle". Journal of Molecular Biology. 339 (2): 313–25.
doi:
10.1016/j.jmb.2004.03.071.
PMID15136035.
^Kojic S, Nestorovic A, Rakicevic L, Protic O, Jasnic-Savovic J, Faulkner G, Radojkovic D (Mar 2015). "Cardiac transcription factor Nkx2.5 interacts with p53 and modulates its activity". Archives of Biochemistry and Biophysics. 569: 45–53.
doi:
10.1016/j.abb.2015.02.001.
PMID25677450.
^Barash IA, Bang ML, Mathew L, Greaser ML, Chen J, Lieber RL (Jul 2007). "Structural and regulatory roles of muscle ankyrin repeat protein family in skeletal muscle". American Journal of Physiology. Cell Physiology. 293 (1): C218–27.
doi:
10.1152/ajpcell.00055.2007.
PMID17392382.
S2CID29659381.
^Barash IA, Mathew L, Ryan AF, Chen J, Lieber RL (Feb 2004). "Rapid muscle-specific gene expression changes after a single bout of eccentric contractions in the mouse". American Journal of Physiology. Cell Physiology. 286 (2): C355–64.
doi:
10.1152/ajpcell.00211.2003.
PMID14561590.
^Witt CC, Ono Y, Puschmann E, McNabb M, Wu Y, Gotthardt M, Witt SH, Haak M, Labeit D, Gregorio CC, Sorimachi H, Granzier H, Labeit S (Feb 2004). "Induction and myofibrillar targeting of CARP, and suppression of the Nkx2.5 pathway in the MDM mouse with impaired titin-based signaling". Journal of Molecular Biology. 336 (1): 145–54.
doi:
10.1016/j.jmb.2003.12.021.
PMID14741210.
^Lehti TM, Silvennoinen M, Kivelä R, Kainulainen H, Komulainen J (Feb 2007). "Effects of streptozotocin-induced diabetes and physical training on gene expression of titin-based stretch-sensing complexes in mouse striated muscle". American Journal of Physiology. Endocrinology and Metabolism. 292 (2): E533–42.
doi:
10.1152/ajpendo.00229.2006.
PMID17003243.
S2CID23964462.
^Nakamura K, Nakada C, Takeuchi K, Osaki M, Shomori K, Kato S, Ohama E, Sato K, Fukayama M, Mori S, Ito H, Moriyama M (2002). "Altered expression of cardiac ankyrin repeat protein and its homologue, ankyrin repeat protein with PEST and proline-rich region, in atrophic muscles in amyotrophic lateral sclerosis". Pathobiology. 70 (4): 197–203.
doi:
10.1159/000069329.
PMID12679596.
S2CID37199318.
Sosovec V, Ivicic L, Gaspar I, L'Achová B (1975). "[Incidence of benign conjugated hyperbilirubinemia with pigment in the liver in Spis (Dubin-Johnson syndrome) II. Attempts at screening of carrier state by means of BSP test]". Cesk Gastroenterol Vyz. 29 (8): 517–26.
PMID1204005.
Pallavicini A, Kojić S, Bean C, Vainzof M, Salamon M, Ievolella C, Bortoletto G, Pacchioni B, Zatz M, Lanfranchi G, Faulkner G, Valle G (2001). "Characterization of human skeletal muscle Ankrd2". Biochem. Biophys. Res. Commun. 285 (2): 378–86.
doi:
10.1006/bbrc.2001.5131.
PMID11444853.
Moriyama M, Tsukamoto Y, Fujiwara M, Kondo G, Nakada C, Baba T, Ishiguro N, Miyazaki A, Nakamura K, Hori N, Sato K, Shomori K, Takeuchi K, Satoh H, Mori S, Ito H (2001). "Identification of a novel human ankyrin-repeated protein homologous to CARP". Biochem. Biophys. Res. Commun. 285 (3): 715–23.
doi:
10.1006/bbrc.2001.5216.
PMID11453652.
Nakamura K, Nakada C, Takeuchi K, Osaki M, Shomori K, Kato S, Ohama E, Sato K, Fukayama M, Mori S, Ito H, Moriyama M (2003). "Altered expression of cardiac ankyrin repeat protein and its homologue, ankyrin repeat protein with PEST and proline-rich region, in atrophic muscles in amyotrophic lateral sclerosis". Pathobiology. 70 (4): 197–203.
doi:
10.1159/000069329.
PMID12679596.
S2CID37199318.
Miller MK, Bang ML, Witt CC, Labeit D, Trombitas C, Watanabe K, Granzier H, McElhinny AS, Gregorio CC, Labeit S (2003). "The muscle ankyrin repeat proteins: CARP, ankrd2/Arpp and DARP as a family of titin filament-based stress response molecules". J. Mol. Biol. 333 (5): 951–64.
doi:
10.1016/j.jmb.2003.09.012.
PMID14583192.