Group:MUZIC:ANKRD2

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Contents

ANKRD2

Introduction

Ankyrin repeat-containing protein 2 (stretch responsive muscle) Ankrd2 belongs to the conserved muscle ankyrin repeat protein (MARP) family[1] also known as ARPP[2]. It is mainly expressed in then skeletal muscle and less in the cardiac muscle, preferentially in type 1 fibers[3]. Ankrd2 shares approximately 50% sequence homology with two more MARP family members: the cardiac ankyrin repeat protein (CARP/Ankrd1) and the diabetes related ankyrin repeat protein DARP. Expression of Ankrd2/Arpp is induced in response to various forms of stress and is highly responsive to muscle mechanical status both in vivo and in vitro[1],[4], as well as to muscle plasticity induced by physical exercise[5],[6]. Apart from the mechanosensory function, Ankrd2/Arpp is a negative regulator of muscle differentiation[7].

Sequence Annotation

Ankrd2 is comprising 360 amino acids and all sequences are available in Uniprot: human, mouse, bovine.

Structure of a designed ankyrin repeat protein (DARPin) with five ankyrin repeat motifs (PDB entry: 2qyj)

Drag the structure with the mouse to rotate

Structure

The ankrd2 gene contains 9 exons and spans about 12 kb. The 280 bp long region upstream of the transcription initiation site of the human Ankrd2 gene is sufficient to confer spatial and temporal expression specificity and contains mainly cis-elements specific for the muscle-specific transcription factor MyoD and for NF-kB[8]. The ankrd2 promoter activity is significantly up-regulated by Nkx2.5[9] upon longitudinal stretch by Akt-dependent NF-kB signaling pathway and in response to transverse stretch by Raf-1-dependent AP-1 signaling pathway[10]. The major structural characteristic of the Ankrd2 protein is the presence in the middle portion of four conserved copies of the 33-residue ankyrin repeats. In addition, Ankrd2 contains a coiled-coil domain that contributes to its self-dimerization, a nuclear localization signal (NLS) allowing its sorting to the nucleus, a PEST protein degradation sequence and numerous potential modification sites mainly for phosphorylation. In particular the phosphorylation of Ankrd2 by the serine/threonine kinase Akt2 is important for its function in muscle differentiation[11]. The position of Ankrd2 phosphorylation by Akt2 is Ser72 which is in close proximity of a calpain3 cleavage site (Arg 77). There are many other consensus phosphorylation sites for casein kinase I (CKI), casein kinase II (CKII), protein kinase C (PKC), extracellular signal regulated kinase (ERK), cAMP- dependent protein kinase, calmodulin-dependent protein kinase II and cGMP-dependent protein kinase [2],[4].


Domain architecture and modification sites of Ankrd2
Domain architecture and modification sites of Ankrd2


Gene Function and Interactions

Ankrd2 is involved in muscle stress response. It is up-regulated after chronic immobilization in a stretched position[1],[6], after eccentric contraction[5], as well as in injured muscles[11]. Denervation of slow muscle decreases the level of Ankrd2 to below the detection limit in 4 weeks [6], whereas denervation of fast muscle increases its expression.[3] Ankrd2 is found in the central I-band of the sarcomere, where binds the N2A region of titin. In myoblasts Ankrd2 localizes both in the nuclei, in form of speckles and in the cytoplasm[7], with a diffused pattern. As the differentiation into multinucleated myotubes progresses, Ankrd2 seems to change localization and to accumulate mainly in the cytoplasm[12]. In general, Ankrd2 protein functions by suffling between the sarcomere and the nucleus, mainly in response to stress signals[13]. Ankrd2 is not essential for the basal functioning of skeletal muscle, but it is clear its influence on the gene expression program of skeletal muscle cells[14]. Mainly the Ankrd2 protein has a major role in skeletal muscle formation as a myogenic regulator since its over-expression in C2C12 myoblasts significantly affects and down-regulates MyoD, myogenin and their target gene Myh1[7].


Pathology

Altered expression of Ankrd2 has been found in patients suffering from inherited myopathies (muscular dystrophies (MD), congenital myopathies (CM)) and motor neuron diseases (spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS)).The Ankrd2/Arpp can interact with titin[4], telethonin/T-cap[13], calpain 3[15], promyelocytic leukemia protein (PML)[13], YB-1[13], p53[13], Akt2[11] and zonula occludens 1 (ZO1)[9].


References

  1. ↑ 1.0 1.1 1.2 Kemp TJ, Sadusky TJ, Saltisi F, Carey N, Moss J, Yang SY, Sassoon DA, Goldspink G, Coulton GR. Identification of Ankrd2, a novel skeletal muscle gene coding for a stretch-responsive ankyrin-repeat protein. Genomics. 2000 Jun 15;66(3):229-41. PMID:10873377 doi:10.1006/geno.2000.6213
  2. ↑ 2.0 2.1 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. Identification of a novel human ankyrin-repeated protein homologous to CARP. Biochem Biophys Res Commun. 2001 Jul 20;285(3):715-23. PMID:11453652 doi:10.1006/bbrc.2001.5216
  3. ↑ 3.0 3.1 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. Arpp, a new homolog of carp, is preferentially expressed in type 1 skeletal muscle fibers and is markedly induced by denervation. Lab Invest. 2002 May;82(5):645-55. PMID:12004005
  4. ↑ 4.0 4.1 4.2 Miller MK, Bang ML, Witt CC, Labeit D, Trombitas C, Watanabe K, Granzier H, McElhinny AS, Gregorio CC, Labeit S. The muscle ankyrin repeat proteins: CARP, ankrd2/Arpp and DARP as a family of titin filament-based stress response molecules. J Mol Biol. 2003 Nov 7;333(5):951-64. PMID:14583192
  5. ↑ 5.0 5.1 Barash IA, Mathew L, Ryan AF, Chen J, Lieber RL. Rapid muscle-specific gene expression changes after a single bout of eccentric contractions in the mouse. Am J Physiol Cell Physiol. 2004 Feb;286(2):C355-64. Epub 2003 Oct 15. PMID:14561590 doi:10.1152/ajpcell.00211.2003
  6. ↑ 6.0 6.1 6.2 Mckoy G, Hou Y, Yang SY, Vega Avelaira D, Degens H, Goldspink G, Coulton GR. 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. 2005 Jun;98(6):2337-43; discussion 2320. Epub 2005 Jan 27. PMID:15677738 doi:10.1152/japplphysiol.01046.2004
  7. ↑ 7.0 7.1 7.2 Bean C, Facchinello N, Faulkner G, Lanfranchi G. The effects of Ankrd2 alteration indicate its involvement in cell cycle regulation during muscle differentiation. Biochim Biophys Acta. 2008 Jun;1783(6):1023-35. Epub 2008 Feb 14. PMID:18302940 doi:10.1016/j.bbamcr.2008.01.027
  8. ↑ Pallavicini A, Kojic S, Bean C, Vainzof M, Salamon M, Ievolella C, Bortoletto G, Pacchioni B, Zatz M, Lanfranchi G, Faulkner G, Valle G. Characterization of human skeletal muscle Ankrd2. Biochem Biophys Res Commun. 2001 Jul 13;285(2):378-86. PMID:11444853 doi:10.1006/bbrc.2001.5131
  9. ↑ 9.0 9.1 Belgrano A, Rakicevic L, Mittempergher L, Campanaro S, Martinelli VC, Mouly V, Valle G, Kojic S, Faulkner G. Multi-tasking role of the mechanosensing protein Ankrd2 in the signaling network of striated muscle. PLoS One. 2011;6(10):e25519. Epub 2011 Oct 10. PMID:22016770 doi:10.1371/journal.pone.0025519
  10. ↑ Mohamed JS, Lopez MA, Cox GA, Boriek AM. Anisotropic regulation of Ankrd2 gene expression in skeletal muscle by mechanical stretch. FASEB J. 2010 Sep;24(9):3330-40. Epub 2010 May 4. PMID:20442316 doi:10.1096/fj.10-158386
  11. ↑ 11.0 11.1 11.2 Cenni V, Bavelloni A, Beretti F, Tagliavini F, Manzoli L, Lattanzi G, Maraldi NM, Cocco L, Marmiroli S. Ankrd2/ARPP is a Novel Akt2 Specific Substrate and Regulates Myogenic Differentiation Upon Cellular Exposure to H2O2. Mol Biol Cell. 2011 Jul 7. PMID:21737686 doi:10.1091/mbc.E10-11-0928
  12. ↑ Pallavicini A, Kojic S, Bean C, Vainzof M, Salamon M, Ievolella C, Bortoletto G, Pacchioni B, Zatz M, Lanfranchi G, Faulkner G, Valle G. Characterization of human skeletal muscle Ankrd2. Biochem Biophys Res Commun. 2001 Jul 13;285(2):378-86. PMID:11444853 doi:10.1006/bbrc.2001.5131
  13. ↑ 13.0 13.1 13.2 13.3 13.4 Kojic S, Medeot E, Guccione E, Krmac H, Zara I, Martinelli V, Valle G, Faulkner G. The Ankrd2 protein, a link between the sarcomere and the nucleus in skeletal muscle. J Mol Biol. 2004 May 28;339(2):313-25. PMID:15136035 doi:10.1016/j.jmb.2004.03.071
  14. ↑ Barash IA, Bang ML, Mathew L, Greaser ML, Chen J, Lieber RL. Structural and regulatory roles of muscle ankyrin repeat protein family in skeletal muscle. Am J Physiol Cell Physiol. 2007 Jul;293(1):C218-27. Epub 2007 Mar 28. PMID:17392382 doi:10.1152/ajpcell.00055.2007
  15. ↑ Hayashi C, Ono Y, Doi N, Kitamura F, Tagami M, Mineki R, Arai T, Taguchi H, Yanagida M, Hirner S, Labeit D, Labeit S, Sorimachi H. Multiple molecular interactions implicate the connectin/titin N2A region as a modulating scaffold for p94/calpain 3 activity in skeletal muscle. J Biol Chem. 2008 May 23;283(21):14801-14. Epub 2008 Feb 29. PMID:18310072 doi:10.1074/jbc.M708262200
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