ANKRD2

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ANKRD2
Identifiers
Aliases ANKRD2, ankyrin repeat domain 2 (stretch responsive muscle), ARPP, ankyrin repeat domain 2
External IDs MGI: 1861447 HomoloGene: 10568 GeneCards: 26287
RNA expression pattern
PBB GE ANKRD2 221232 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_020349
NM_001129981
NM_001291218
NM_001291219

NM_020033

RefSeq (protein)

NP_001123453.1
NP_001278147.1
NP_001278148.1
NP_065082.2

NP_064417.1

Location (UCSC) Chr 10: 97.57 – 97.58 Mb Chr 19: 42.04 – 42.05 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/Edit Mouse

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 ANKRD2 gene.[1][2][3][4] 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 AARP has been shown to be altered in patients with dilated cardiomyopathy and amyotrophic lateral sclerosis.

Structure[edit]

Two isoforms of ARPP have been documented; a 39.8 kDa protein isoform composed of 360 amino acids[5] and a 36.2 kDa protein isoform composed of 327 amino acids.[6] 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.[7][8] It has been proposed that AARP can homo- or hetero-dimerize with other MARPs in an antiparallel fashion.[9] ARPP is highly expressed in nuclei and I-bands in slow skeletal fibers[7][10] and cardiac muscle, specifically in ventricular regions[8] at intercalated discs;[11] and expression in brain, pancreas and esophageal epithelium has also been documented.[10][12] 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.[13]

Function[edit]

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.[13] 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.[14] It was further demonstrated that Nkx2.5 and p53 synergistically activate the ANKRD2 promoter to promote effects on myogenic differentiation.[15] 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.[9] 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.[16] 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.[17]

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.[10] 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.[18] 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.[19] Levels of AARP were also altered in a mouse model of diabetes.[20]

Clinical Significance[edit]

In patients with dilated cardiomyopathy, levels of AARP were upregulated.[21]

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.[22]

ARPP has also been shown to be a potentially useful biomarker for the differential diagnosis between oncocytoma and chromophobe renal cell carcinomas.[23]

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.[24]

Interactions[edit]

ANKRD2 has been shown to interact with

References[edit]

  1. ^ 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. PMID 10873377. 
  2. ^ a b c d e 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". J. Mol. Biol. 339 (2): 313–25. doi:10.1016/j.jmb.2004.03.071. PMID 15136035. 
  3. ^ 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. PMID 15677738. 
  4. ^ "Entrez Gene: ANKRD2 ankyrin repeat domain 2 (stretch responsive muscle)". 
  5. ^ "Protein sequence of human ANKRD2 (Uniprot ID: Q9GZV1)". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Retrieved 25 June 2015. 
  6. ^ "Protein sequence of human ANKRD2 (Uniprot ID: Q9GZV1-2)". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). 
  7. ^ a b Pallavicini 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. PMID 11444853. 
  8. ^ a b 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 (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. PMID 11453652. 
  9. ^ a b Lun AS, Chen J, Lange S (Sep 2014). "Probing muscle ankyrin-repeat protein (MARP) structure and function". Anatomical Record 297 (9): 1615–29. doi:10.1002/ar.22968. PMID 25125175. 
  10. ^ a b c Tsukamoto Y, Senda T, Nakano T, Nakada C, Hida T, Ishiguro N, Kondo G, Baba T, Sato K, Osaki M, Mori S, Ito H, Moriyama M (May 2002). "Arpp, a new homolog of carp, is preferentially expressed in type 1 skeletal muscle fibers and is markedly induced by denervation". Laboratory Investigation 82 (5): 645–55. doi:10.1038/labinvest.3780459. PMID 12004005. 
  11. ^ 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. PMID 25585647. 
  12. ^ 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. PMID 21500110. 
  13. ^ a b Ishiguro N, Baba T, Ishida T, Takeuchi K, Osaki M, Araki N, Okada E, Takahashi S, Saito M, Watanabe M, Nakada C, Tsukamoto Y, Sato K, Ito K, Fukayama M, Mori S, Ito H, Moriyama M (May 2002). "Carp, a cardiac ankyrin-repeated protein, and its new homologue, Arpp, are differentially expressed in heart, skeletal muscle, and rhabdomyosarcomas". The American Journal of Pathology 160 (5): 1767–78. doi:10.1016/S0002-9440(10)61123-6. PMID 12000728. 
  14. ^ 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. PMID 15136035. 
  15. ^ 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. PMID 25677450. 
  16. ^ 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. PMID 17392382. 
  17. ^ Bang ML, Gu Y, Dalton ND, Peterson KL, Chien KR, Chen J (2014). "The muscle ankyrin repeat proteins CARP, Ankrd2, and DARP are not essential for normal cardiac development and function at basal conditions and in response to pressure overload". PLOS ONE 9 (4): e93638. doi:10.1371/journal.pone.0093638. PMID 24736439. 
  18. ^ 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. PMID 14561590. 
  19. ^ 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. PMID 14741210. 
  20. ^ 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. PMID 17003243. 
  21. ^ Nagueh SF, Shah G, Wu Y, Torre-Amione G, King NM, Lahmers S, Witt CC, Becker K, Labeit S, Granzier HL (Jul 2004). "Altered titin expression, myocardial stiffness, and left ventricular function in patients with dilated cardiomyopathy". Circulation 110 (2): 155–62. doi:10.1161/01.CIR.0000135591.37759.AF. PMID 15238456. 
  22. ^ 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. PMID 12679596. 
  23. ^ Shomori K, Nagashima Y, Kuroda N, Honjo A, Tsukamoto Y, Tokuyasu N, Maeta N, Matsuura K, Hijiya N, Yano S, Yokoyama S, Ito H, Moriyama M (Feb 2007). "ARPP protein is selectively expressed in renal oncocytoma, but rarely in renal cell carcinomas". Modern Pathology 20 (2): 199–207. doi:10.1038/modpathol.3800730. PMID 17206105. 
  24. ^ Lehti M, Kivelä R, Komi P, Komulainen J, Kainulainen H, Kyröläinen H (Apr 2009). "Effects of fatiguing jumping exercise on mRNA expression of titin-complex proteins and calpains". Journal of Applied Physiology 106 (4): 1419–24. doi:10.1152/japplphysiol.90660.2008. PMID 19150862. 
  25. ^ Miller MK, Bang ML, Witt CC, Labeit D, Trombitas C, Watanabe K, Granzier H, McElhinny AS, Gregorio CC, Labeit S (Nov 2003). "The muscle ankyrin repeat proteins: CARP, ankrd2/Arpp and DARP as a family of titin filament-based stress response molecules". Journal of Molecular Biology 333 (5): 951–64. doi:10.1016/j.jmb.2003.09.012. PMID 14583192. 

Further reading[edit]

  • 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. PMID 1204005. 
  • 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. PMID 11444853. 
  • 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. PMID 11453652. 
  • Laveder P, De Pittà C, Toppo S, Valle G, Lanfranchi G (2002). "A two-step strategy for constructing specifically self-subtracted cDNA libraries". Nucleic Acids Res. 30 (9): e38. doi:10.1093/nar/30.9.e38. PMC 113861. PMID 11972353. 
  • Tsukamoto Y, Senda T, Nakano T, Nakada C, Hida T, Ishiguro N, Kondo G, Baba T, Sato K, Osaki M, Mori S, Ito H, Moriyama M (2002). "Arpp, a new homolog of carp, is preferentially expressed in type 1 skeletal muscle fibers and is markedly induced by denervation". Lab. Invest. 82 (5): 645–55. doi:10.1038/labinvest.3780459. PMID 12004005. 
  • 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. PMID 12679596. 
  • 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. PMID 14583192. 
  • Ishiguro N, Motoi T, Osaki M, Araki N, Minamizaki T, Moriyama M, Ito H, Yoshida H (2005). "Immunohistochemical analysis of a muscle ankyrin-repeat protein, Arpp, in paraffin-embedded tumors: evaluation of Arpp as a tumor marker for rhabdomyosarcoma". Hum. Pathol. 36 (6): 620–5. doi:10.1016/j.humpath.2005.04.014. PMID 16021567. 
  • Shomori K, Nagashima Y, Kuroda N, Honjo A, Tsukamoto Y, Tokuyasu N, Maeta N, Matsuura K, Hijiya N, Yano S, Yokoyama S, Ito H, Moriyama M (2007). "ARPP protein is selectively expressed in renal oncocytoma, but rarely in renal cell carcinomas". Mod. Pathol. 20 (2): 199–207. doi:10.1038/modpathol.3800730. PMID 17206105.