Skip to main content

Advertisement

SpringerLink
Log in

The phospho-landscape of the survival of motoneuron protein (SMN) protein: relevance for spinal muscular atrophy (SMA)

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Spinal muscular atrophy (SMA) is caused by low levels of the survival of motoneuron (SMN) Protein leading to preferential degeneration of lower motoneurons in the ventral horn of the spinal cord and brain stem. However, the SMN protein is ubiquitously expressed and there is growing evidence of a multisystem phenotype in SMA. Since a loss of SMN function is critical, it is important to decipher the regulatory mechanisms of SMN function starting on the level of the SMN protein itself. Posttranslational modifications (PTMs) of proteins regulate multiple functions and processes, including activity, cellular trafficking, and stability. Several PTM sites have been identified within the SMN sequence. Here, we map the identified SMN PTMs highlighting phosphorylation as a key regulator affecting localization, stability and functions of SMN. Furthermore, we propose SMN phosphorylation as a crucial factor for intracellular interaction and cellular distribution of SMN. We outline the relevance of phosphorylation of the spinal muscular atrophy (SMA) gene product SMN with regard to basic housekeeping functions of SMN impaired in this neurodegenerative disease. Finally, we compare SMA patient mutations with putative and verified phosphorylation sites. Thus, we emphasize the importance of phosphorylation as a cellular modulator in a clinical perspective as a potential additional target for combinatorial SMA treatment strategies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Availability of data and material

Not applicable.

References

  1. Crawford TO et al (1999) Abnormal fatty acid metabolism in childhood spinal muscular atrophy. Ann Neurol 45(3):337–343. https://doi.org/10.1002/1531-8249(199903)45:3%3c337::aid-ana9%3e3.0.co;2-u

    Article  CAS  PubMed  Google Scholar 

  2. Wijngaarde CA et al (2017) Cardiac pathology in spinal muscular atrophy: a systematic review. Orphanet J Rare Dis 12(1):67. https://doi.org/10.1186/s13023-017-0613-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Nery FC et al (2019) Impaired kidney structure and function in spinal muscular atrophy. Neurol Genet 5(5):e353. https://doi.org/10.1212/NXG.0000000000000353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hua Y et al (2011) Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Nature 478(7367):123–126. https://doi.org/10.1038/nature10485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hamilton G, Gillingwater TH (2013) Spinal muscular atrophy: going beyond the motor neuron. Trends Mol Med 19(1):40–50. https://doi.org/10.1016/j.molmed.2012.11.002

    Article  CAS  PubMed  Google Scholar 

  6. Szunyogova E et al (2016) Survival Motor Neuron (SMN) protein is required for normal mouse liver development. Sci Rep 6:34635. https://doi.org/10.1038/srep34635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Deguise MO et al (2019) Abnormal fatty acid metabolism is a core component of spinal muscular atrophy. Ann Clin Transl Neurol 6(8):1519–1532. https://doi.org/10.1002/acn3.50855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Vitte JM et al (2004) Deletion of murine Smn exon 7 directed to liver leads to severe defect of liver development associated with iron overload. Am J Pathol 165(5):1731–1741. https://doi.org/10.1016/S0002-9440(10)63428-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Martinez-Hernandez R et al (2009) The developmental pattern of myotubes in spinal muscular atrophy indicates prenatal delay of muscle maturation. J Neuropathol Exp Neurol 68(5):474–481. https://doi.org/10.1097/NEN.0b013e3181a10ea1

    Article  PubMed  Google Scholar 

  10. Allardyce H et al (2020) Renal pathology in a mouse model of severe Spinal Muscular Atrophy is associated with downregulation of Glial Cell-Line Derived Neurotrophic Factor (GDNF). Hum Mol Genet 29(14):2365–2378. https://doi.org/10.1093/hmg/ddaa126

    Article  CAS  PubMed  Google Scholar 

  11. Hensel N et al (2020) Altered bone development with impaired cartilage formation precedes neuromuscular symptoms in spinal muscular atrophy. Hum Mol Genet 29(16):2662–2673. https://doi.org/10.1093/hmg/ddaa145

    Article  CAS  PubMed  Google Scholar 

  12. Lefebvre S et al (1995) Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80(1):155–165. https://doi.org/10.1016/0092-8674(95)90460-3

    Article  CAS  PubMed  Google Scholar 

  13. Lorson CL et al (1999) A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci USA 96(11):6307–6311. https://doi.org/10.1073/pnas.96.11.6307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Monani UR (2005) Spinal muscular atrophy: a deficiency in a ubiquitous protein; a motor neuron-specific disease. Neuron 48(6):885–896. https://doi.org/10.1016/j.neuron.2005.12.001

    Article  CAS  PubMed  Google Scholar 

  15. Lefebvre S et al (1997) Correlation between severity and SMN protein level in spinal muscular atrophy. Nat Genet 16(3):265–269. https://doi.org/10.1038/ng0797-265

    Article  CAS  PubMed  Google Scholar 

  16. Burghes AH, Beattie CE (2009) Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick? Nat Rev Neurosci 10(8):597–609. https://doi.org/10.1038/nrn2670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. D’Amico A et al (2011) Spinal muscular atrophy. Orphanet J Rare Dis 6:71. https://doi.org/10.1186/1750-1172-6-71

    Article  PubMed  PubMed Central  Google Scholar 

  18. Dubowitz V (1999) Very severe spinal muscular atrophy (SMA type 0): an expanding clinical phenotype. Eur J Paediatr Neurol 3(2):49–51. https://doi.org/10.1053/ejpn.1999.0181

    Article  CAS  PubMed  Google Scholar 

  19. Feldkotter M et al (2002) Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy. Am J Hum Genet 70(2):358–368. https://doi.org/10.1086/338627

    Article  CAS  PubMed  Google Scholar 

  20. Kolb SJ, Kissel JT (2015) Spinal muscular atrophy. Neurol Clin 33(4):831–846. https://doi.org/10.1016/j.ncl.2015.07.004

    Article  PubMed  PubMed Central  Google Scholar 

  21. Wirth B et al (2006) Mildly affected patients with spinal muscular atrophy are partially protected by an increased SMN2 copy number. Hum Genet 119(4):422–428. https://doi.org/10.1007/s00439-006-0156-7

    Article  CAS  PubMed  Google Scholar 

  22. Ottesen EW (2017) ISS-N1 makes the First FDA-approved drug for spinal muscular atrophy. Transl Neurosci 8:1–6. https://doi.org/10.1515/tnsci-2017-0001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Finkel RS et al (2017) Nusinersen versus Sham control in infantile-onset spinal muscular atrophy. N Engl J Med 377(18):1723–1732. https://doi.org/10.1056/NEJMoa1702752

    Article  CAS  PubMed  Google Scholar 

  24. Mercuri E et al (2018) Nusinersen versus Sham control in later-onset spinal muscular atrophy. N Engl J Med 378(7):625–635. https://doi.org/10.1056/NEJMoa1710504

    Article  CAS  PubMed  Google Scholar 

  25. Ratni H et al (2018) Discovery of risdiplam, a selective survival of motor neuron-2 ( SMN2) gene splicing modifier for the treatment of spinal muscular atrophy (SMA). J Med Chem 61(15):6501–6517. https://doi.org/10.1021/acs.jmedchem.8b00741

    Article  CAS  PubMed  Google Scholar 

  26. Meyer K et al (2015) Improving single injection CSF delivery of AAV9-mediated gene therapy for SMA: a dose-response study in mice and nonhuman primates. Mol Ther 23(3):477–487. https://doi.org/10.1038/mt.2014.210

    Article  CAS  PubMed  Google Scholar 

  27. Mendell JR et al (2017) Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med 377(18):1713–1722. https://doi.org/10.1056/NEJMoa1706198

    Article  CAS  PubMed  Google Scholar 

  28. Al-Zaidy S et al (2019) Health outcomes in spinal muscular atrophy type 1 following AVXS-101 gene replacement therapy. Pediatr Pulmonol 54(2):179–185. https://doi.org/10.1002/ppul.24203

    Article  PubMed  Google Scholar 

  29. Hensel N, Kubinski S, Claus P (2020) The need for SMN-independent treatments of spinal muscular atrophy (SMA) to complement SMN-enhancing drugs. Front Neurol 11:45. https://doi.org/10.3389/fneur.2020.00045

    Article  PubMed  PubMed Central  Google Scholar 

  30. Grimmler M et al (2005) Phosphorylation regulates the activity of the SMN complex during assembly of spliceosomal U snRNPs. EMBO Rep 6(1):70–76. https://doi.org/10.1038/sj.embor.7400301

    Article  CAS  PubMed  Google Scholar 

  31. Husedzinovic A et al (2014) Phosphoregulation of the human SMN complex. Eur J Cell Biol 93(3):106–117. https://doi.org/10.1016/j.ejcb.2014.01.006

    Article  CAS  PubMed  Google Scholar 

  32. Wu CY et al (2011) Identification of the phosphorylation sites in the survival motor neuron protein by protein kinase A. Biochim Biophys Acta 1814(9):1134–1139. https://doi.org/10.1016/j.bbapap.2011.04.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Rademacher S et al (2020) A single amino acid residue regulates PTEN-binding and stability of the spinal muscular atrophy protein SMN. Cells. https://doi.org/10.3390/cells9112405

    Article  PubMed  PubMed Central  Google Scholar 

  34. Lorson CL, Androphy EJ (1998) The domain encoded by exon 2 of the survival motor neuron protein mediates nucleic acid binding. Hum Mol Genet 7(8):1269–1275. https://doi.org/10.1093/hmg/7.8.1269

    Article  CAS  PubMed  Google Scholar 

  35. van Bergeijk J et al (2007) The spinal muscular atrophy gene product regulates neurite outgrowth: importance of the C terminus. FASEB J 21(7):1492–1502. https://doi.org/10.1096/fj.06-7136com

    Article  CAS  PubMed  Google Scholar 

  36. Pellizzoni L et al (1998) A novel function for SMN, the spinal muscular atrophy disease gene product, in pre-mRNA splicing. Cell 95(5):615–624. https://doi.org/10.1016/s0092-8674(00)81632-3

    Article  CAS  PubMed  Google Scholar 

  37. Martin R et al (2012) The survival motor neuron protein forms soluble glycine zipper oligomers. Structure 20(11):1929–1939. https://doi.org/10.1016/j.str.2012.08.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wang J, Dreyfuss G (2001) Characterization of functional domains of the SMN protein in vivo. J Biol Chem 276(48):45387–45393. https://doi.org/10.1074/jbc.M105059200

    Article  CAS  PubMed  Google Scholar 

  39. Fuller HR et al (2010) The SMN interactome includes Myb-binding protein 1a. J Proteome Res 9(1):556–563. https://doi.org/10.1021/pr900884g

    Article  CAS  PubMed  Google Scholar 

  40. Fuller HR, Gillingwater TH, Wishart TM (2016) Commonality amid diversity: Multi-study proteomic identification of conserved disease mechanisms in spinal muscular atrophy. Neuromuscul Disord 26(9):560–569. https://doi.org/10.1016/j.nmd.2016.06.004

    Article  PubMed  Google Scholar 

  41. Lauria F et al (2020) SMN-primed ribosomes modulate the translation of transcripts related to spinal muscular atrophy. Nat Cell Biol 22(10):1239–1251. https://doi.org/10.1038/s41556-020-00577-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wirth B (2021) Spinal muscular atrophy: in the challenge lies a solution. Trends Neurosci 44(4):306–322. https://doi.org/10.1016/j.tins.2020.11.009

    Article  CAS  PubMed  Google Scholar 

  43. Nölle A et al (2011) The spinal muscular atrophy disease protein SMN is linked to the Rho-kinase pathway via profilin. Hum Mol Genet 20(24):4865–4878. https://doi.org/10.1093/hmg/ddr425

    Article  CAS  PubMed  Google Scholar 

  44. Hensel N, Claus P (2018) The actin cytoskeleton in SMA and ALS: how does it contribute to motoneuron degeneration? Neuroscientist 24(1):54–72. https://doi.org/10.1177/1073858417705059

    Article  CAS  PubMed  Google Scholar 

  45. Liu Q et al (1997) The spinal muscular atrophy disease gene product, SMN, and its associated protein SIP1 are in a complex with spliceosomal snRNP proteins. Cell 90(6):1013–1021. https://doi.org/10.1016/s0092-8674(00)80367-0

    Article  CAS  PubMed  Google Scholar 

  46. Gubitz AK, Feng W, Dreyfuss G (2004) The SMN complex. Exp Cell Res 296(1):51–56. https://doi.org/10.1016/j.yexcr.2004.03.022

    Article  CAS  PubMed  Google Scholar 

  47. Feng W et al (2005) Gemins modulate the expression and activity of the SMN complex. Hum Mol Genet 14(12):1605–1611. https://doi.org/10.1093/hmg/ddi168

    Article  CAS  PubMed  Google Scholar 

  48. Forthmann B, Grothe C, Claus P (2015) A nuclear odyssey: fibroblast growth factor-2 (FGF-2) as a regulator of nuclear homeostasis in the nervous system. Cell Mol Life Sci 72(9):1651–1662. https://doi.org/10.1007/s00018-014-1818-6

    Article  CAS  PubMed  Google Scholar 

  49. Takizawa Y et al (2010) GEMIN2 promotes accumulation of RAD51 at double-strand breaks in homologous recombination. Nucleic Acids Res 38(15):5059–5074. https://doi.org/10.1093/nar/gkq271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kannan A et al (2020) ZPR1 prevents R-loop accumulation, upregulates SMN2 expression and rescues spinal muscular atrophy. Brain 143(1):69–93. https://doi.org/10.1093/brain/awz373

    Article  PubMed  Google Scholar 

  51. Pagliardini S et al (2000) Subcellular localization and axonal transport of the survival motor neuron (SMN) protein in the developing rat spinal cord. Hum Mol Genet 9(1):47–56

    Article  CAS  Google Scholar 

  52. Kariya S et al (2008) Reduced SMN protein impairs maturation of the neuromuscular junctions in mouse models of spinal muscular atrophy. Hum Mol Genet 17(16):2552–2569. https://doi.org/10.1093/hmg/ddn156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Dimitriadi M et al (2016) Decreased function of survival motor neuron protein impairs endocytic pathways. Proc Natl Acad Sci USA 113(30):E4377–E4386. https://doi.org/10.1073/pnas.1600015113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Lorson CL, Androphy EJ (2000) An exonic enhancer is required for inclusion of an essential exon in the SMA-determining gene SMN. Hum Mol Genet 9(2):259–265. https://doi.org/10.1093/hmg/9.2.259

    Article  CAS  PubMed  Google Scholar 

  55. Setola V et al (2007) Axonal-SMN (a-SMN), a protein isoform of the survival motor neuron gene, is specifically involved in axonogenesis. Proc Natl Acad Sci USA 104(6):1959–1964. https://doi.org/10.1073/pnas.0610660104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Seo J et al (2016) A novel human-specific splice isoform alters the critical C-terminus of survival motor neuron protein. Sci Rep 6:30778. https://doi.org/10.1038/srep30778

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Chaytow H et al (2018) The role of survival motor neuron protein (SMN) in protein homeostasis. Cell Mol Life Sci 75(21):3877–3894. https://doi.org/10.1007/s00018-018-2849-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Osman EY et al (2019) Functional characterization of SMN evolution in mouse models of SMA. Sci Rep 9(1):9472. https://doi.org/10.1038/s41598-019-45822-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Ogawa C et al (2007) Gemin2 plays an important role in stabilizing the survival of motor neuron complex. J Biol Chem 282(15):11122–11134. https://doi.org/10.1074/jbc.M609297200

    Article  CAS  PubMed  Google Scholar 

  60. Young PJ et al (2002) A direct interaction between the survival motor neuron protein and p53 and its relationship to spinal muscular atrophy. J Biol Chem 277(4):2852–2859. https://doi.org/10.1074/jbc.M108769200

    Article  CAS  PubMed  Google Scholar 

  61. Sprangers R et al (2003) High-resolution X-ray and NMR structures of the SMN Tudor domain: conformational variation in the binding site for symmetrically dimethylated arginine residues. J Mol Biol 327(2):507–520

    Article  CAS  Google Scholar 

  62. Tripsianes K et al (2011) Structural basis for dimethylarginine recognition by the Tudor domains of human SMN and SPF30 proteins. Nat Struct Mol Biol 18(12):1414–1420. https://doi.org/10.1038/nsmb.2185

    Article  CAS  PubMed  Google Scholar 

  63. Buhler D et al (1999) Essential role for the tudor domain of SMN in spliceosomal U snRNP assembly: implications for spinal muscular atrophy. Hum Mol Genet 8(13):2351–2357

    Article  CAS  Google Scholar 

  64. Pellizzoni L et al (2001) The survival of motor neurons (SMN) protein interacts with the snoRNP proteins fibrillarin and GAR1. Curr Biol 11(14):1079–1088. https://doi.org/10.1016/s0960-9822(01)00316-5

    Article  CAS  PubMed  Google Scholar 

  65. Mourelatos Z et al (2001) SMN interacts with a novel family of hnRNP and spliceosomal proteins. EMBO J 20(19):5443–5452. https://doi.org/10.1093/emboj/20.19.5443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Rossoll W et al (2002) Specific interaction of Smn, the spinal muscular atrophy determining gene product, with hnRNP-R and gry-rbp/hnRNP-Q: a role for Smn in RNA processing in motor axons? Hum Mol Genet 11(1):93–105. https://doi.org/10.1093/hmg/11.1.93

    Article  CAS  PubMed  Google Scholar 

  67. Yamazaki T et al (2012) FUS-SMN protein interactions link the motor neuron diseases ALS and SMA. Cell Rep 2(4):799–806. https://doi.org/10.1016/j.celrep.2012.08.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Sabra M et al (2013) The Tudor protein survival motor neuron (SMN) is a chromatin-binding protein that interacts with methylated lysine 79 of histone H3. J Cell Sci 126(Pt 16):3664–3677. https://doi.org/10.1242/jcs.126003

    Article  CAS  PubMed  Google Scholar 

  69. Zhao DY et al (2016) SMN and symmetric arginine dimethylation of RNA polymerase II C-terminal domain control termination. Nature 529(7584):48–53. https://doi.org/10.1038/nature16469

    Article  CAS  PubMed  Google Scholar 

  70. Hebert MD et al (2001) Coilin forms the bridge between Cajal bodies and SMN, the spinal muscular atrophy protein. Genes Dev 15(20):2720–2729. https://doi.org/10.1101/gad.908401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Claus P, Bruns AF, Grothe C (2004) Fibroblast growth factor-2(23) binds directly to the survival of motoneuron protein and is associated with small nuclear RNAs. Biochem J 384(Pt 3):559–565. https://doi.org/10.1042/BJ20040801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Lorson CL et al (1998) SMN oligomerization defect correlates with spinal muscular atrophy severity. Nat Genet 19(1):63–66. https://doi.org/10.1038/ng0598-63

    Article  CAS  PubMed  Google Scholar 

  73. Ardito F et al (2017) The crucial role of protein phosphorylation in cell signaling and its use as targeted therapy (review). Int J Mol Med 40(2):271–280. https://doi.org/10.3892/ijmm.2017.3036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Mann M et al (2002) Analysis of protein phosphorylation using mass spectrometry: deciphering the phosphoproteome. Trends Biotechnol 20(6):261–268. https://doi.org/10.1016/s0167-7799(02)01944-3

    Article  CAS  PubMed  Google Scholar 

  75. Keenan EK, Zachman DK, Hirschey MD (2021) Discovering the landscape of protein modifications. Mol Cell 81(9):1868–1878. https://doi.org/10.1016/j.molcel.2021.03.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Levene PA, Alsberg CL (1906) The cleavage products of vitellin. J Biol Chem 2(1):127–133. https://doi.org/10.1016/S0021-9258(17)46054-6

    Article  Google Scholar 

  77. Lipmann F (1983) Analysis of phosphoproteins and developments in protein phosphorylation. Trends Biochem Sci 8(9):334–336. https://doi.org/10.1016/0968-0004(83)90105-6

    Article  CAS  Google Scholar 

  78. Ghosh S, Marrocco I, Yarden Y (2020) Roles for receptor tyrosine kinases in tumor progression and implications for cancer treatment. Adv Cancer Res 147:1–57. https://doi.org/10.1016/bs.acr.2020.04.002

    Article  PubMed  Google Scholar 

  79. Thompson JD, Higgins DG, Gibson TJ (1994) CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 22(22):4673–4680. https://doi.org/10.1093/nar/22.22.4673

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Schilling M et al (2021) TOR signaling regulates liquid phase separation of the SMN complex governing snRNP biogenesis. Cell Rep 35(12):109277. https://doi.org/10.1016/j.celrep.2021.109277

    Article  CAS  PubMed  Google Scholar 

  81. Rikova K et al (2007) Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 131(6):1190–1203. https://doi.org/10.1016/j.cell.2007.11.025

    Article  CAS  PubMed  Google Scholar 

  82. Hornbeck PV et al (2015) PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Nucl Acids Res 43:D512–D520. https://doi.org/10.1093/nar/gku1267

    Article  CAS  PubMed  Google Scholar 

  83. Weber C, Schreiber TB, Daub H (2012) Dual phosphoproteomics and chemical proteomics analysis of erlotinib and gefitinib interference in acute myeloid leukemia cells. J Proteom 75(4):1343–1356. https://doi.org/10.1016/j.jprot.2011.11.004

    Article  CAS  Google Scholar 

  84. Danielsen JM et al (2011) Mass spectrometric analysis of lysine ubiquitylation reveals promiscuity at site level. Mol Cell Proteom. https://doi.org/10.1074/mcp.M110.003590

    Article  Google Scholar 

  85. Kim W et al (2011) Systematic and quantitative assessment of the ubiquitin-modified proteome. Mol Cell 44(2):325–340. https://doi.org/10.1016/j.molcel.2011.08.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Wagner SA et al (2011) A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles. Mol Cell Proteom. https://doi.org/10.1074/mcp.M111.013284

    Article  Google Scholar 

  87. Han KJ et al (2012) Ubiquitin-specific protease 9x deubiquitinates and stabilizes the spinal muscular atrophy protein-survival motor neuron. J Biol Chem 287(52):43741–43752. https://doi.org/10.1074/jbc.M112.372318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Akimov V et al (2018) UbiSite approach for comprehensive mapping of lysine and N-terminal ubiquitination sites. Nat Struct Mol Biol 25(7):631–640. https://doi.org/10.1038/s41594-018-0084-y

    Article  CAS  PubMed  Google Scholar 

  89. Sharma K et al (2014) Ultradeep human phosphoproteome reveals a distinct regulatory nature of Tyr and Ser/Thr-based signaling. Cell Rep 8(5):1583–1594. https://doi.org/10.1016/j.celrep.2014.07.036

    Article  CAS  PubMed  Google Scholar 

  90. Rigbolt KT et al (2011) System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation. Sci Signal 4(164):rs3. https://doi.org/10.1126/scisignal.2001570

    Article  PubMed  Google Scholar 

  91. Lafarga V et al (2018) CBP-mediated SMN acetylation modulates Cajal body biogenesis and the cytoplasmic targeting of SMN. Cell Mol Life Sci 75(3):527–546. https://doi.org/10.1007/s00018-017-2638-2

    Article  CAS  PubMed  Google Scholar 

  92. Tapia O et al (2014) The SMN Tudor SIM-like domain is key to SmD1 and coilin interactions and to Cajal body biogenesis. J Cell Sci 127(Pt 5):939–946. https://doi.org/10.1242/jcs.138537

    Article  CAS  PubMed  Google Scholar 

  93. Mertins P et al (2016) Proteogenomics connects somatic mutations to signalling in breast cancer. Nature 534(7605):55–62. https://doi.org/10.1038/nature18003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Carrier M et al (2016) Phosphoproteome and transcriptome of RA-responsive and RA-resistant breast cancer cell lines. PLoS ONE 11(6):e0157290. https://doi.org/10.1371/journal.pone.0157290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Kettenbach AN et al (2011) Quantitative phosphoproteomics identifies substrates and functional modules of Aurora and Polo-like kinase activities in mitotic cells. Sci Signal 4(179):rs5. https://doi.org/10.1126/scisignal.2001497

    Article  CAS  PubMed  Google Scholar 

  96. Guo A et al (2014) Immunoaffinity enrichment and mass spectrometry analysis of protein methylation. Mol Cell Proteom 13(1):372–387. https://doi.org/10.1074/mcp.O113.027870

    Article  CAS  Google Scholar 

  97. Povlsen LK et al (2012) Systems-wide analysis of ubiquitylation dynamics reveals a key role for PAF15 ubiquitylation in DNA-damage bypass. Nat Cell Biol 14(10):1089–1098. https://doi.org/10.1038/ncb2579

    Article  CAS  PubMed  Google Scholar 

  98. Alias L et al (2009) Mutation update of spinal muscular atrophy in Spain: molecular characterization of 745 unrelated patients and identification of four novel mutations in the SMN1 gene. Hum Genet 125(1):29–39. https://doi.org/10.1007/s00439-008-0598-1

    Article  CAS  PubMed  Google Scholar 

  99. Wirth B (2000) An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Hum Mutat 15(3):228–237. https://doi.org/10.1002/(SICI)1098-1004(200003)15:3%3c228::AID-HUMU3%3e3.0.CO;2-9

    Article  CAS  PubMed  Google Scholar 

  100. Wirth B et al (1999) Quantitative analysis of survival motor neuron copies: identification of subtle SMN1 mutations in patients with spinal muscular atrophy, genotype-phenotype correlation, and implications for genetic counseling. Am J Hum Genet 64(5):1340–1356. https://doi.org/10.1086/302369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Janku F et al (2012) PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. J Clin Oncol 30(8):777–782. https://doi.org/10.1200/JCO.2011.36.1196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Parmenter TJ et al (2014) Response of BRAF-mutant melanoma to BRAF inhibition is mediated by a network of transcriptional regulators of glycolysis. Cancer Discov 4(4):423–433. https://doi.org/10.1158/2159-8290.CD-13-0440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Kobashigawa Y et al (2011) Autoinhibition and phosphorylation-induced activation mechanisms of human cancer and autoimmune disease-related E3 protein Cbl-b. Proc Natl Acad Sci USA 108(51):20579–20584. https://doi.org/10.1073/pnas.1110712108

    Article  PubMed  PubMed Central  Google Scholar 

  104. Samovski D et al (2015) Regulation of AMPK activation by CD36 links fatty acid uptake to beta-oxidation. Diabetes 64(2):353–359. https://doi.org/10.2337/db14-0582

    Article  CAS  PubMed  Google Scholar 

  105. Forlenza OV et al (2011) Increased platelet GSK3B activity in patients with mild cognitive impairment and Alzheimer’s disease. J Psychiatr Res 45(2):220–224. https://doi.org/10.1016/j.jpsychires.2010.06.002

    Article  PubMed  Google Scholar 

  106. Nolle A et al (2011) The spinal muscular atrophy disease protein SMN is linked to the Rho-kinase pathway via profilin. Hum Mol Genet 20(24):4865–4878. https://doi.org/10.1093/hmg/ddr425

    Article  CAS  PubMed  Google Scholar 

  107. Iyer CC et al (2018) Mild SMN missense alleles are only functional in the presence of SMN2 in mammals. Hum Mol Genet 27(19):3404–3416. https://doi.org/10.1093/hmg/ddy251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Ruhno C et al (2019) Complete sequencing of the SMN2 gene in SMA patients detects SMN gene deletion junctions and variants in SMN2 that modify the SMA phenotype. Hum Genet 138(3):241–256. https://doi.org/10.1007/s00439-019-01983-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Wang CC et al (2010) Multi-exon genotyping of SMN gene in spinal muscular atrophy by universal fluorescent PCR and capillary electrophoresis. Electrophoresis 31(14):2396–2404. https://doi.org/10.1002/elps.201000124

    Article  CAS  PubMed  Google Scholar 

  110. Gray KM et al (2018) Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCF(Slmb) degron. Mol Biol Cell 29(2):96–110. https://doi.org/10.1091/mbc.E17-11-0627

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Pellizzoni L, Charroux B, Dreyfuss G (1999) SMN mutants of spinal muscular atrophy patients are defective in binding to snRNP proteins. Proc Natl Acad Sci USA 96(20):11167–11172. https://doi.org/10.1073/pnas.96.20.11167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Tsai CH et al (2001) Molecular analysis of SMN, NAIP and P44 genes of SMA patients and their families. J Neurol Sci 190(1–2):35–40. https://doi.org/10.1016/s0022-510x(01)00574-3

    Article  CAS  PubMed  Google Scholar 

  113. Yu-Jin Q et al (2012) Subtle mutations in the SMN1 gene in Chinese patients with SMA: p.Arg288Met mutation causing SMN1 transcript exclusion of exon7. BMC Med Genet 13:86. https://doi.org/10.1186/1471-2350-13-86

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Qu YJ et al (2016) Mutation spectrum of the survival of motor neuron 1 and functional analysis of variants in chinese spinal muscular atrophy. J Mol Diagn 18(5):741–752. https://doi.org/10.1016/j.jmoldx.2016.05.004

    Article  CAS  PubMed  Google Scholar 

  115. Fraidakis MJ et al (2012) Genotype-phenotype relationship in 2 SMA III patients with novel mutations in the Tudor domain. Neurology 78(8):551–556. https://doi.org/10.1212/WNL.0b013e318247ca69

    Article  CAS  PubMed  Google Scholar 

  116. Prior TW (2007) Spinal muscular atrophy diagnostics. J Child Neurol 22(8):952–956. https://doi.org/10.1177/0883073807305668

    Article  PubMed  Google Scholar 

  117. Cao YY et al (2018) Diagnosis of spinal muscular atrophy: a simple method for quantifying the relative amount of survival motor neuron gene 1/2 using sanger DNA sequencing. Chin Med J (Engl) 131(24):2921–2929. https://doi.org/10.4103/0366-6999.247198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Hahnen E et al (1997) Missense mutations in exon 6 of the survival motor neuron gene in patients with spinal muscular atrophy (SMA). Hum Mol Genet 6(5):821–825. https://doi.org/10.1093/hmg/6.5.821

    Article  CAS  PubMed  Google Scholar 

  119. Sun Y et al (2005) Molecular and functional analysis of intragenic SMN1 mutations in patients with spinal muscular atrophy. Hum Mutat 25(1):64–71. https://doi.org/10.1002/humu.20111

    Article  CAS  PubMed  Google Scholar 

  120. Rochette CF et al (1997) Molecular diagnosis of non-deletion SMA patients using quantitative PCR of SMN exon 7. Neurogenetics 1(2):141–147. https://doi.org/10.1007/s100480050021

    Article  CAS  PubMed  Google Scholar 

  121. Clermont O et al (2004) Molecular analysis of SMA patients without homozygous SMN1 deletions using a new strategy for identification of SMN1 subtle mutations. Hum Mutat 24(5):417–427. https://doi.org/10.1002/humu.20092

    Article  CAS  PubMed  Google Scholar 

  122. Parsons DW et al (1998) Diagnosis of spinal muscular atrophy in an SMN non-deletion patient using a quantitative PCR screen and mutation analysis. J Med Genet 35(8):674–676. https://doi.org/10.1136/jmg.35.8.674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Pellizzoni L (2007) Chaperoning ribonucleoprotein biogenesis in health and disease. EMBO Rep 8(4):340–345. https://doi.org/10.1038/sj.embor.7400941

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Tapia O et al (2012) Reorganization of Cajal bodies and nucleolar targeting of coilin in motor neurons of type I spinal muscular atrophy. Histochem Cell Biol 137(5):657–667. https://doi.org/10.1007/s00418-012-0921-8

    Article  CAS  PubMed  Google Scholar 

  125. Liu Q, Dreyfuss G (1996) A novel nuclear structure containing the survival of motor neurons protein. EMBO J 15(14):3555–3565

    Article  CAS  Google Scholar 

  126. Hebert MD (2010) Phosphorylation and the Cajal body: modification in search of function. Arch Biochem Biophys 496(2):69–76. https://doi.org/10.1016/j.abb.2010.02.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Young PJ et al (2000) The relationship between SMN, the spinal muscular atrophy protein, and nuclear coiled bodies in differentiated tissues and cultured cells. Exp Cell Res 256(2):365–374. https://doi.org/10.1006/excr.2000.4858

    Article  CAS  PubMed  Google Scholar 

  128. Raska I et al (1990) Association between the nucleolus and the coiled body. J Struct Biol 104(1–3):120–127. https://doi.org/10.1016/1047-8477(90)90066-l

    Article  CAS  PubMed  Google Scholar 

  129. Li DK et al (2014) SMN control of RNP assembly: from post-transcriptional gene regulation to motor neuron disease. Semin Cell Dev Biol 32:22–29. https://doi.org/10.1016/j.semcdb.2014.04.026

    Article  CAS  PubMed  Google Scholar 

  130. Chari A et al (2008) An assembly chaperone collaborates with the SMN complex to generate spliceosomal SnRNPs. Cell 135(3):497–509. https://doi.org/10.1016/j.cell.2008.09.020

    Article  CAS  PubMed  Google Scholar 

  131. Singh RN et al (2017) Diverse role of survival motor neuron protein. Biochim Biophys Acta 1860(3):299–315. https://doi.org/10.1016/j.bbagrm.2016.12.008

    Article  CAS  PubMed Central  Google Scholar 

  132. Galcheva-Gargova Z et al (1998) The cytoplasmic zinc finger protein ZPR1 accumulates in the nucleolus of proliferating cells. Mol Biol Cell 9(10):2963–2971. https://doi.org/10.1091/mbc.9.10.2963

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Gangwani L et al (1998) Interaction of ZPR1 with translation elongation factor-1alpha in proliferating cells. J Cell Biol 143(6):1471–1484. https://doi.org/10.1083/jcb.143.6.1471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Gangwani L, Flavell RA, Davis RJ (2005) ZPR1 is essential for survival and is required for localization of the survival motor neurons (SMN) protein to Cajal bodies. Mol Cell Biol 25(7):2744–2756. https://doi.org/10.1128/MCB.25.7.2744-2756.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Mishra AK et al (2007) Structural insights into the interaction of the evolutionarily conserved ZPR1 domain tandem with eukaryotic EF1A, receptors, and SMN complexes. Proc Natl Acad Sci USA 104(35):13930–13935. https://doi.org/10.1073/pnas.0704915104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Galcheva-Gargova Z et al (1996) Binding of zinc finger protein ZPR1 to the epidermal growth factor receptor. Science 272(5269):1797–1802. https://doi.org/10.1126/science.272.5269.1797

    Article  CAS  PubMed  Google Scholar 

  137. Gangwani L et al (2001) Spinal muscular atrophy disrupts the interaction of ZPR1 with the SMN protein. Nat Cell Biol 3(4):376–383. https://doi.org/10.1038/35070059

    Article  CAS  PubMed  Google Scholar 

  138. Helmken C et al (2003) Evidence for a modifying pathway in SMA discordant families: reduced SMN level decreases the amount of its interacting partners and Htra2-beta1. Hum Genet 114(1):11–21. https://doi.org/10.1007/s00439-003-1025-2

    Article  CAS  PubMed  Google Scholar 

  139. Jiang X, Kannan A, Gangwani L (2019) ZPR1-dependent neurodegeneration is mediated by the JNK signaling pathway. J Exp Neurosci 13:1179069519867915. https://doi.org/10.1177/1179069519867915

    Article  PubMed  PubMed Central  Google Scholar 

  140. Burnett BG et al (2009) Regulation of SMN protein stability. Mol Cell Biol 29(5):1107–1115. https://doi.org/10.1128/MCB.01262-08

    Article  CAS  PubMed  Google Scholar 

  141. Husedzinovic A et al (2015) The catalytically inactive tyrosine phosphatase HD-PTP/PTPN23 is a novel regulator of SMN complex localization. Mol Biol Cell 26(2):161–171. https://doi.org/10.1091/mbc.E14-06-1151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Cohen PT (1997) Novel protein serine/threonine phosphatases: variety is the spice of life. Trends Biochem Sci 22(7):245–251

    Article  CAS  Google Scholar 

  143. Carnegie GK et al (2003) Protein phosphatase 4 interacts with the Survival of Motor Neurons complex and enhances the temporal localisation of snRNPs. J Cell Sci 116(Pt 10):1905–1913. https://doi.org/10.1242/jcs.00409

    Article  CAS  PubMed  Google Scholar 

  144. Kloeker S, Wadzinski BE (1999) Purification and identification of a novel subunit of protein serine/threonine phosphatase 4. J Biol Chem 274(9):5339–5347. https://doi.org/10.1074/jbc.274.9.5339

    Article  CAS  PubMed  Google Scholar 

  145. Brewis ND, Cohen PT (1992) Protein phosphatase X has been highly conserved during mammalian evolution. Biochim Biophys Acta 1171(2):231–233. https://doi.org/10.1016/0167-4781(92)90129-n

    Article  CAS  PubMed  Google Scholar 

  146. Hastie CJ et al (2000) A novel 50 kDa protein forms complexes with protein phosphatase 4 and is located at centrosomal microtubule organizing centres. Biochem J 347(Pt 3):845–855

    Article  CAS  Google Scholar 

  147. Virshup DM, Shenolikar S (2009) From promiscuity to precision: protein phosphatases get a makeover. Mol Cell 33(5):537–545. https://doi.org/10.1016/j.molcel.2009.02.015

    Article  CAS  PubMed  Google Scholar 

  148. Bollen M et al (2010) The extended PP1 toolkit: designed to create specificity. Trends Biochem Sci 35(8):450–458. https://doi.org/10.1016/j.tibs.2010.03.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Berndt N, Dohadwala M, Liu CWY (1997) Constitutively active protein phosphatase 1α causes Rb-dependent G1 arrest in human cancer cells. Curr Biol 7(6):375–386. https://doi.org/10.1016/S0960-9822(06)00185-0

    Article  CAS  PubMed  Google Scholar 

  150. Fong NM et al (2000) Identification of binding sites on protein targeting to glycogen for enzymes of glycogen metabolism*. J Biol Chem 275(45):35034–35039. https://doi.org/10.1074/jbc.M005541200

    Article  CAS  PubMed  Google Scholar 

  151. Allen PB et al (2006) Distinct roles for spinophilin and neurabin in dopamine-mediated plasticity. Neuroscience 140(3):897–911. https://doi.org/10.1016/j.neuroscience.2006.02.067

    Article  CAS  PubMed  Google Scholar 

  152. Bao Z et al (2016) Protein phosphatase 1γ regulates the proliferation of human glioma via the NF-κB pathway. Oncol Rep 35(5):2916–2926. https://doi.org/10.3892/or.2016.4644

    Article  CAS  PubMed  Google Scholar 

  153. Renvoise B et al (2012) A role for protein phosphatase PP1gamma in SMN complex formation and subnuclear localization to Cajal bodies. J Cell Sci 125(Pt 12):2862–2874. https://doi.org/10.1242/jcs.096255

    Article  CAS  PubMed  Google Scholar 

  154. Lammers T, Lavi S (2007) Role of type 2C protein phosphatases in growth regulation and in cellular stress signaling. Crit Rev Biochem Mol Biol 42(6):437–461. https://doi.org/10.1080/10409230701693342

    Article  CAS  PubMed  Google Scholar 

  155. Murray MV, Kobayashi R, Krainer AR (1999) The type 2C Ser/Thr phosphatase PP2Cgamma is a pre-mRNA splicing factor. Genes Dev 13(1):87–97. https://doi.org/10.1101/gad.13.1.87

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. McNamara RP et al (2013) Transcription factors mediate the enzymatic disassembly of promoter-bound 7SK snRNP to locally recruit P-TEFb for transcription elongation. Cell Rep 5(5):1256–1268. https://doi.org/10.1016/j.celrep.2013.11.003

    Article  CAS  PubMed  Google Scholar 

  157. Gudipaty SA et al (2015) PPM1G Binds 7SK RNA and hexim1 to block P-TEFb assembly into the 7SK snRNP and sustain transcription elongation. Mol Cell Biol 35(22):3810–3828. https://doi.org/10.1128/mcb.00226-15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Petri S et al (2007) Dephosphorylation of survival motor neurons (SMN) by PPM1G/PP2Cgamma governs Cajal body localization and stability of the SMN complex. J Cell Biol 179(3):451–465. https://doi.org/10.1083/jcb.200704163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Toyooka S et al (2000) HD-PTP: a novel protein tyrosine phosphatase gene on human chromosome 3p21.3. Biochem Biophys Res Commun 278(3):671–678. https://doi.org/10.1006/bbrc.2000.3870

    Article  CAS  PubMed  Google Scholar 

  160. Cao L et al (1998) A novel putative protein-tyrosine phosphatase contains a BRO1-like domain and suppresses Ha-ras-mediated transformation. J Biol Chem 273(33):21077–21083. https://doi.org/10.1074/jbc.273.33.21077

    Article  CAS  PubMed  Google Scholar 

  161. Doyotte A et al (2008) The Bro1-related protein HD-PTP/PTPN23 is required for endosomal cargo sorting and multivesicular body morphogenesis. Proc Natl Acad Sci 105(17):6308. https://doi.org/10.1073/pnas.0707601105

    Article  PubMed  PubMed Central  Google Scholar 

  162. Gingras MC et al (2009) Expression analysis and essential role of the putative tyrosine phosphatase His-domain-containing protein tyrosine phosphatase (HD-PTP). Int J Dev Biol 53(7):1069–1074. https://doi.org/10.1387/ijdb.082820mg

    Article  CAS  PubMed  Google Scholar 

  163. Bivik C et al (2015) Novel genes involved in controlling specification of drosophila FMR famide neuropeptide cells. Genetics 200(4):1229–1244. https://doi.org/10.1534/genetics.115.178483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Bend R et al (2020) Phenotype and mutation expansion of the PTPN23 associated disorder characterized by neurodevelopmental delay and structural brain abnormalities. Eur J Hum Genet 28(1):76–87. https://doi.org/10.1038/s41431-019-0487-1

    Article  CAS  PubMed  Google Scholar 

  165. Bononi A, Pinton P (2015) Study of PTEN subcellular localization. Methods 77–78:92–103. https://doi.org/10.1016/j.ymeth.2014.10.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Stambolic V et al (1998) Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95(1):29–39. https://doi.org/10.1016/s0092-8674(00)81780-8

    Article  CAS  PubMed  Google Scholar 

  167. Rahdar M et al (2009) A phosphorylation-dependent intramolecular interaction regulates the membrane association and activity of the tumor suppressor PTEN. Proc Natl Acad Sci 106(2):480–485. https://doi.org/10.1073/pnas.0811212106

    Article  PubMed  Google Scholar 

  168. Gabanella F et al (2007) Ribonucleoprotein assembly defects correlate with spinal muscular atrophy severity and preferentially affect a subset of spliceosomal snRNPs. PLoS ONE 2(9):e921. https://doi.org/10.1371/journal.pone.0000921

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Ning K et al (2010) PTEN depletion rescues axonal growth defect and improves survival in SMN-deficient motor neurons. Hum Mol Genet 19(16):3159–3168. https://doi.org/10.1093/hmg/ddq226

    Article  CAS  PubMed  Google Scholar 

  170. Blom N, Gammeltoft S, Brunak S (1999) Sequence and structure-based prediction of eukaryotic protein phosphorylation sites. J Mol Biol 294(5):1351–1362. https://doi.org/10.1006/jmbi.1999.3310

    Article  CAS  PubMed  Google Scholar 

  171. Blom N et al (2004) Prediction of post-translational glycosylation and phosphorylation of proteins from the amino acid sequence. Proteomics 4(6):1633–1649. https://doi.org/10.1002/pmic.200300771

    Article  CAS  PubMed  Google Scholar 

  172. Wong YH et al (2007) KinasePhos 2.0: a web server for identifying protein kinase-specific phosphorylation sites based on sequences and coupling patterns. Nucleic Acids Res 35:W588–W594. https://doi.org/10.1093/nar/gkm322

    Article  PubMed  PubMed Central  Google Scholar 

  173. Wang C et al (2020) GPS 50: an update on the prediction of kinase-specific phosphorylation sites in proteins. Genom Proteom Bioinf 18(1):72–80. https://doi.org/10.1016/j.gpb.2020.01.001

    Article  CAS  Google Scholar 

  174. Bah A, Forman-Kay JD (2016) Modulation of intrinsically disordered protein function by post-translational modifications. J Biol Chem 291(13):6696–6705. https://doi.org/10.1074/jbc.R115.695056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Knorre DG, Kudryashova NV, Godovikova TS (2009) Chemical and functional aspects of posttranslational modification of proteins. Acta Nat 1(3):29–51

    Article  CAS  Google Scholar 

  176. Hebert MD, Poole AR (2017) Towards an understanding of regulating Cajal body activity by protein modification. RNA Biol 14(6):761–778. https://doi.org/10.1080/15476286.2016.1243649

    Article  PubMed  Google Scholar 

  177. Chang HC et al (2004) Degradation of survival motor neuron (SMN) protein is mediated via the ubiquitin/proteasome pathway. Neurochem Int 45(7):1107–1112. https://doi.org/10.1016/j.neuint.2004.04.005

    Article  CAS  PubMed  Google Scholar 

  178. Kwon DY et al (2011) Increasing expression and decreasing degradation of SMN ameliorate the spinal muscular atrophy phenotype in mice. Hum Mol Genet 20(18):3667–3677. https://doi.org/10.1093/hmg/ddr288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Hsu SH et al (2010) Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) regulates the level of SMN expression through ubiquitination in primary spinal muscular atrophy fibroblasts. Clin Chim Acta 411(23–24):1920–1928. https://doi.org/10.1016/j.cca.2010.07.035

    Article  CAS  PubMed  Google Scholar 

  180. Powis RA et al (2014) Increased levels of UCHL1 are a compensatory response to disrupted ubiquitin homeostasis in spinal muscular atrophy and do not represent a viable therapeutic target. Neuropathol Appl Neurobiol 40(7):873–887. https://doi.org/10.1111/nan.12168

    Article  CAS  PubMed  Google Scholar 

  181. Kwon JE, Kim EK, Choi EJ (2011) Stabilization of the survival motor neuron protein by ASK1. FEBS Lett 585(9):1287–1292. https://doi.org/10.1016/j.febslet.2011.04.011

    Article  CAS  PubMed  Google Scholar 

  182. Kwon DY et al (2013) The E3 ubiquitin ligase mind bomb 1 ubiquitinates and promotes the degradation of survival of motor neuron protein. Mol Biol Cell 24(12):1863–1871. https://doi.org/10.1091/mbc.E13-01-0042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Han KJ et al (2016) Monoubiquitination of survival motor neuron regulates its cellular localization and Cajal body integrity. Hum Mol Genet 25(7):1392–1405. https://doi.org/10.1093/hmg/ddw021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Johnson ES (2004) Protein modification by SUMO. Annu Rev Biochem 73:355–382. https://doi.org/10.1146/annurev.biochem.73.011303.074118

    Article  CAS  PubMed  Google Scholar 

  185. Kerscher O (2007) SUMO junction-what’s your function? New insights through SUMO-interacting motifs. EMBO Rep 8(6):550–555. https://doi.org/10.1038/sj.embor.7400980

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Riboldi GM et al (2021) Sumoylation regulates the assembly and activity of the SMN complex. Nat Commun 12(1):5040. https://doi.org/10.1038/s41467-021-25272-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Allfrey VG, Faulkner R, Mirsky AE (1964) Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis. Proc Natl Acad Sci U S A 51:786–794. https://doi.org/10.1073/pnas.51.5.786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Choudhary C et al (2014) The growing landscape of lysine acetylation links metabolism and cell signalling. Nat Rev Mol Cell Biol 15(8):536–550. https://doi.org/10.1038/nrm3841

    Article  CAS  PubMed  Google Scholar 

  189. Verdin E, Ott M (2015) 50 years of protein acetylation: from gene regulation to epigenetics, metabolism and beyond. Nat Rev Mol Cell Biol 16(4):258–264. https://doi.org/10.1038/nrm3931

    Article  CAS  PubMed  Google Scholar 

  190. Korzus E, Rosenfeld MG, Mayford M (2004) CBP histone acetyltransferase activity is a critical component of memory consolidation. Neuron 42(6):961–972. https://doi.org/10.1016/j.neuron.2004.06.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Bekesi A et al (2018) Challenges in the structural-functional characterization of multidomain, partially disordered proteins CBP and p300: preparing native proteins and developing nanobody tools. Methods Enzymol 611:607–675. https://doi.org/10.1016/bs.mie.2018.09.032

    Article  CAS  PubMed  Google Scholar 

  192. Selenko P et al (2001) SMN tudor domain structure and its interaction with the Sm proteins. Nat Struct Biol 8(1):27–31. https://doi.org/10.1038/83014

    Article  CAS  PubMed  Google Scholar 

  193. Jenuwein T, Allis CD (2001) Translating the histone code. Science 293(5532):1074–1080. https://doi.org/10.1126/science.1063127

    Article  CAS  PubMed  Google Scholar 

  194. Bedford MT, Richard S (2005) Arginine methylation an emerging regulator of protein function. Mol Cell 18(3):263–272. https://doi.org/10.1016/j.molcel.2005.04.003

    Article  CAS  PubMed  Google Scholar 

  195. Cote J, Richard S (2005) Tudor domains bind symmetrical dimethylated arginines. J Biol Chem 280(31):28476–28483. https://doi.org/10.1074/jbc.M414328200

    Article  CAS  PubMed  Google Scholar 

  196. Brahms H et al (2001) Symmetrical dimethylation of arginine residues in spliceosomal Sm protein B/B’ and the Sm-like protein LSm4, and their interaction with the SMN protein. RNA 7(11):1531–1542. https://doi.org/10.1017/s135583820101442x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Needham EJ et al (2019) Illuminating the dark phosphoproteome. Sci Signal. https://doi.org/10.1126/scisignal.aau8645

    Article  PubMed  Google Scholar 

  198. Sievers F et al (2011) Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol Syst Biol 7:539. https://doi.org/10.1038/msb.2011.75

    Article  PubMed  PubMed Central  Google Scholar 

  199. Vaughan TG (2017) IcyTree: rapid browser-based visualization for phylogenetic trees and networks. Bioinformatics 33(15):2392–2394. https://doi.org/10.1093/bioinformatics/btx155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank members of the Claus group for discussions, and especially Amy Glynn for suggestions on the text. Moreover, we are grateful for funding by the Deutsche Muskelstiftung (SMAPERIPHERAL) and SMA Europe (SMATARGET).

Funding

We are grateful for funding by the Deutsche Muskelstiftung (SMAPERIPHERAL) and SMA Europe (SMATARGET).

Author information

Author notes

  1. Nora Tula Detering and Tobias Schüning contributed equally to this work.

Authors and Affiliations

  1. SMATHERIA gGmbH – Non-Profit Biomedical Research Institute, Hannover, Germany

    Nora Tula Detering, Tobias Schüning & Peter Claus

  2. Ottawa Hospital Research Institute (OHRI), Ottawa, Canada

    Niko Hensel

  3. Center for Systems Neuroscience (ZSN), Hannover, Germany

    Nora Tula Detering, Tobias Schüning, Niko Hensel & Peter Claus

Authors
  1. Nora Tula Detering
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tobias Schüning
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Niko Hensel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peter Claus
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the preparation, writing, and final approval of the manuscript.

Corresponding author

Correspondence to Peter Claus.

Ethics declarations

Conflict of interest

All authors declared no competing interests.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

18_2022_4522_MOESM1_ESM.png

Supplementary file1 Supplemental Phylogenetic comparison of SMN primary structures from 24 different species. Primary structures of SMN from 24 different species were aligned by Clustal Omega (program clustalo, version 1.2.4) [198] and a phylogenetic tree was generated as a neighbor-joining tree without distance corrections. The alignment was visualized by IcyTree software [199]. (PNG 17 kb)

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Detering, N.T., Schüning, T., Hensel, N. et al. The phospho-landscape of the survival of motoneuron protein (SMN) protein: relevance for spinal muscular atrophy (SMA). Cell. Mol. Life Sci. 79, 497 (2022). https://doi.org/10.1007/s00018-022-04522-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00018-022-04522-9

Keywords

Search

Navigation