Skip to main content
SpringerLink
Log in

Post-translational Regulation of STAR Proteins and Effects on Their Biological Functions

  • Chapter
Post-Transcriptional Regulation by STAR Proteins

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 693))

Abstract

STAR (Signal Transduction and Activation of RNA) proteins owed their name to the presence in their structure of a RNA-binding domain and several hallmarks of their involvement in signal transduction pathways. In many members of the family, the STAR RNA-binding domain (also named GSG, an acronym for GRP33/Sam68/GLD-1) is flanked by regulatory regions containing proline-rich sequences, which serve as docking sites for proteins containing SH3 and WW domains and also a tyrosine-rich region at the C-terminus, which can mediate protein-protein interactions with partners through SH2 domains. These regulatory regions contain consensus sequences for additional modifications, including serine/threonine phosphorylation, methylation, acetylation and sumoylation. Since their initial description, evidence has been gathered in different cell types and model organisms that STAR proteins can indeed integrate signals from external and internal cues with changes in transcription and processing of target RNAs. The most striking example of the high versatility of STAR proteins is provided by Sam68 (KHDRBS1), whose function, subcellular localization and affinity for RNA are strongly modulated by several signaling pathways through specific modifications. Moreover, the recent development of genetic knockout models has unveiled the physiological function of some STAR proteins, pointing to a crucial role of their post-translational modifications in the biological processes regulated by these RNA-binding proteins. This chapter offers an overview of the most updated literature on the regulation of STAR proteins by post-translational modifications and illustrates examples of how signal transduction pathways can modulate their activity and affect biological processes.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Vernet C, Artzt K. STAR, a gene family involved in signal transduction and activation of RNA. Trends Genet 1997; 13:479–484.

    Article  CAS  PubMed  Google Scholar 

  2. Chen T, Damaj BB, Herrera C et al. Self-association of the single-KH-domain family members Sam68, GRP33, GLD-1 and Qk1: role of the KH domain. Mol Cell Biol 1997; 17:5707–5718.

    CAS  PubMed  Google Scholar 

  3. Lukong KE, Richard S. Sam68, the KH domain-containing superSTAR. Bioch Biophys Acta 2003; 1653:73–86.

    CAS  Google Scholar 

  4. Najib S, Martín-Romero C, González-Yanes C et al. R Role of Sam68 as an adaptor protein in signal transduction. Cell Mol Life Sci 20 2005; 62:36–43

    Article  CAS  Google Scholar 

  5. Paronetto MP, Achsel T, Massiello A et al. The RNA-binding protein Sam68 modulates the alternative splicing of Bcl-x. J Cell Biol 2007; 176:929–939.

    Article  CAS  PubMed  Google Scholar 

  6. Taylor SJ, Anafi M, Pawson T et al. Functional interaction between c-Src and its mitotic target, Sam 68. J Biol Chem 1995; 270:10120–10124.

    Article  CAS  PubMed  Google Scholar 

  7. Wang LL, Richard S, Shaw AS. P62 association with RNA is regulated by tyrosine phosphorylation. J Biol Chem 1995; 270:2010–2013.

    Article  CAS  PubMed  Google Scholar 

  8. Haegebarth A, Heap D, Bie W et al. The nuclear tyrosine kinase BRK/Sik phosphorylates and inhibits the RNA-binding activities of the Sam68-like mammalian proteins SLM-1 and SLM-2. J Biol Chem 2004; 279:54398–54404.

    Article  CAS  PubMed  Google Scholar 

  9. Stoss O, Novoyatleva T, Gencheva M et al. p59(fyn)-mediated phosphorylation regulates the activity of the tissue-specific splicing factor rSLM-1. Mol Cell Neurosci 2004; 27:8–21.

    Article  CAS  PubMed  Google Scholar 

  10. Matter N, Herrlich P, Konig H. Signal-dependent regulation of splicing via phosphorylation of Sam68. Nature 2002; 420:691–695.

    Article  CAS  PubMed  Google Scholar 

  11. Paronetto MP, Zalfa F, Botti F et al. The nuclear RNA-binding protein Sam68 translocates to the cytoplasm and associates with the polysomes in mouse spermatocytes. Mol Biol Cell 2006; 17:14–24.

    Article  CAS  PubMed  Google Scholar 

  12. Paronetto MP, Messina V, Bianchi E et al. Sam68 regulates translation of target mRNAs in male germ cells, necessary for mouse spermatogenesis. J Cell Biol 2009; 185:235–249.

    Article  CAS  PubMed  Google Scholar 

  13. Richard S, Yu D, Blumer KJ et al. Association of p62, a multifunctional SH2-and SH3-domain-binding protein, with src family tyrosine kinases, Grb2 and phospholipase C gamma-1. Mol Cell Biol 1995; 15:186–197.

    CAS  PubMed  Google Scholar 

  14. Li J, Liu Y, Kim BO et al. Direct participation of Sam68, the 68-kilodalton Src-associated protein in mitosis, in the CRM1-mediated Rev nuclear export pathway. J Virol 2002; 76:8374–8382.

    Article  CAS  PubMed  Google Scholar 

  15. Coyle JH, Guzik BW, Bor YC et al. Sam68 enhances the cytoplasmic utilization of intron-containing RNA and is functionally regulated by the nuclear kinase Sik/BRK. Mol Cell Biol 2003; 23:92–103.

    Article  CAS  PubMed  Google Scholar 

  16. Modem S, Badri KR, Holland TC et al. Sam68 is absolutely required for Rev function and HIV-1 production. Nucleic Acids Res 2005;33:873–879.

    Article  CAS  PubMed  Google Scholar 

  17. Cochrane A. Inhibition of HIV-1 gene expression by Sam68 Delta C: multiple targets but a common mechanism? Retrovirology 2009; 6:22.

    Article  PubMed  Google Scholar 

  18. Henao-Mejia J, Liu Y, Park IW et al. Suppression of HIV-1 Nef translation by Sam68 mutant-induced stress granules and nef mRNA sequestration. Mol Cell 2009; 33:87–96.

    Article  CAS  PubMed  Google Scholar 

  19. Hong W, Resnick RJ, Rakowski C et al. Physical and functional interaction between the transcriptional cofactor CBP and the KH domain protein Sam68. Mol Cancer Res 2002; 1:48–55.

    CAS  PubMed  Google Scholar 

  20. Taylor SJ, Resnick RJ, Shalloway D. Sam68 exerts separable effects on cell cycle progression and apoptosis. BMC Cell Biol 2004; 5:5.

    Article  PubMed  Google Scholar 

  21. Batsche E, Ianiv M, Muchardt C. The human SWI/SNF subunit Brm is a regulator of alternative splicing. Nat Struct Mol Biol 2006; 13:22–29.

    Article  CAS  PubMed  Google Scholar 

  22. Rajan P, Gaughan L, Dalgliesh C et al. The RNA-binding and adaptor protein Sam68 modulates signal-dependent splicing and transcriptional activity of the androgen receptor. J Pathol 2008; 215:67–77.

    Article  CAS  PubMed  Google Scholar 

  23. Kornblihtt AR. Coupling transcription and alternative splicing. Adv Exp Med Biol 2007; 623:175–189.

    Article  PubMed  Google Scholar 

  24. Chawla G, Lin CH, Han A et al. Sam68 regulates a set of alternatively spliced exons during neurogenesis. Mol Cell Biol 2009; 29:201–213.

    Article  CAS  PubMed  Google Scholar 

  25. Ben Fredj N, Grange J, Sadoul R et al. Depolarization-induced translocation of the RNA-binding protein Sam68 to the dendrites of hippocampal neurons. J Cell Sci 2004; 117:1079–1090.

    Article  CAS  PubMed  Google Scholar 

  26. Grange J, Belly A, Dupas S et al. Specific interaction between Sam68 and neuronal mRNAs: implication for the activity-dependent biosynthesis of elongation factor eEF1A. J Neurosci Res 2009; 87:12–25.

    Article  CAS  PubMed  Google Scholar 

  27. Paronetto MP, Bianchi E, Geremia R et al. Dynamic expression of the RNA-binding protein Sam68 during mouse pre-implantation development. Gene Expr Patterns 2008; 8:311–322.

    Article  CAS  PubMed  Google Scholar 

  28. Wong G, Müller O, Clark R et al. Molecular cloning and nucleic acid binding properties of the GAP-associated tyrosine phosphoprotein p62. Cell 1992; 69:551–558.

    Article  CAS  PubMed  Google Scholar 

  29. Lock P, Fumagalli S, Polakis P et al. The human p62 cDNA encodes Sam68 and not the RasGAP-associated p62 protein. Cell 1996; 84:23–24.

    Article  CAS  PubMed  Google Scholar 

  30. Taylor SJ, Shalloway D. An RNA-binding protein associated with Src through its SH2 and SH3 domains in mitosis. Nature 1994; 368:867–871.

    Article  CAS  PubMed  Google Scholar 

  31. Fumagalli S, Totty NF, Hsuan JJ et al. A target for Src in mitosis. Nature 1994; 368:871–874.

    Article  CAS  PubMed  Google Scholar 

  32. Jabado N, Pallier A, Le Deist F et al. CD4 ligands inhibit the formation of multifunctional transduction complexes involved in T-cell activation. J Immunol 1997; 158:94–103.

    CAS  PubMed  Google Scholar 

  33. Fusaki N, Iwamatsu A, Iwashima M et al. Interaction between Sam68 and Src family tyrosine kinases, Fyn and Lck, in T-cell receptor signaling. J Biol Chem 1997; 272:6214–6219.

    Article  CAS  PubMed  Google Scholar 

  34. Trüb T, Frantz JD, Miyazaki M et al. The role of a lymphoid-restricted, Grb2-like SH3-SH2-SH3 protein in T-cell receptor signaling. J Biol Chem 1997; 272:894–902.

    Article  PubMed  Google Scholar 

  35. Sánchez-Margalet V, Najib S. Sam68 is a docking protein linking GAP and PI3K in insulin receptor signaling. Mol Cell Endocrinol 2 2001; 183:113–121.

    Article  Google Scholar 

  36. Fresno Vara JA, Cáceres MA et al. Src family kinases are required for prolactin induction of cell proliferation. Mol Biol Cell 2001; 12:2171–2183.

    CAS  PubMed  Google Scholar 

  37. Richard S, Vogel G, Huot ME et al. Sam68 haploinsufficiency delays onset of mammary tumorigenesis and metastasis. Oncogene 2008; 27:548–556.

    Article  CAS  PubMed  Google Scholar 

  38. Lukong KE, Larocque D, Tyner AL et al. Tyrosine phosphorylation of sam68 by breast tumor kinase regulates intranuclear localization and cell cycle progression. J Biol Chem 2005; 280:38639–38647.

    Article  CAS  PubMed  Google Scholar 

  39. Paronetto MP, Farini D, Sammarco I et al. Expression of a truncated form of the c-Kit tyrosine kinase receptor and activation of Src kinase in human prostatic cancer. Am J Pathol 2004; 164:1243–1251.

    CAS  PubMed  Google Scholar 

  40. Paronetto MP, Venables JP, Elliott DJ et al. Tr-kit promotes the formation of a multimolecular complex composed by Fyn, PLCgamma1 and Sam68. Oncogene 2003; 22:8707–8715.

    CAS  PubMed  Google Scholar 

  41. Gorla L, Cantù M, Miccichè F et al. RET oncoproteins induce tyrosine phosphorylation changes of proteins involved in RNA metabolism. Cell Signal 20 2006; 18:2272–2282

    Article  CAS  Google Scholar 

  42. Huot ME, Brown CM, Lamarche-Vane N et al. An adaptor role for cytoplasmic Sam68 in modulating Src activity during cell polarization. Mol Cell Biol 2009; 29:1933–1943.

    Article  CAS  PubMed  Google Scholar 

  43. Andreotti AH, Bunnell SC, Feng S et al. Regulatory intramolecular association in a tyrosine kinase of the Tec family. Nature 1997; 385:93–97.

    Article  CAS  PubMed  Google Scholar 

  44. Guinamard R, Fougereau M, Seckinger P. The SH3 domain of Bruton’s tyrosine kinase interacts with Vav, Sam68 and EWS. Scand J Immunol 1 1997; 45:587–595.

    Article  CAS  Google Scholar 

  45. Lang V, Mège D, Semichon M et al. A dual participation of ZAP-70 and scr protein tyrosine kinases is required for TCR-induced tyrosine phosphorylation of Sam68 in Jurkat T-cells. Eur J Immunol 1 1997; 27:3360–3367.

    Article  CAS  Google Scholar 

  46. Derry JJ, Richard S, Valderrama Carvajal H et al. Sik (BRK) phosphorylates Sam68 in the nucleus and negatively regulates its RNA binding ability. Mol Cell Biol 2000; 20:6114–6126.

    Article  CAS  PubMed  Google Scholar 

  47. Hartmann AM, Nayler O, Schwaiger FW et al. The interaction and colocalization of Sam68 with the splicing-associated factor YT521-B in nuclear dots is regulated by the Src family kinase p59(fyn). Mol Biol Cell 1999; 10:3909–3926.

    CAS  PubMed  Google Scholar 

  48. Derry JJ, Prins GS, Ray V et al. Altered localization and activity of the intracellular tyrosine kinase BRK/Sik in prostate tumor cells. Oncogene 2003; 22:4212–4220.

    Article  CAS  PubMed  Google Scholar 

  49. Busà R, Paronetto MP, Farini D et al. The RNA-binding protein Sam68 contributes to proliferation and survival of human prostate cancer cells. Oncogene 2007; 26:4372–4382.

    Article  PubMed  Google Scholar 

  50. Resnick RJ, Taylor SJ, Lin Q et al. Phosphorylation of the Src substrate Sam68 by Cdc2 during mitosis. Oncogene 1997; 15:1247–1253.

    Article  CAS  PubMed  Google Scholar 

  51. Lee SC, Harn HJ, Lin TS et al. Prognostic significance of CD44v5 expression in human thymic epithelial neoplasms. Ann Thorac Surg 2003; 76:213–218.

    Article  PubMed  Google Scholar 

  52. Tisserant A, König H. Signal-regulated Pre-mRNA occupancy by the general splicing factor U2AF. PLoS One 2008; 3:e1418.

    Article  PubMed  Google Scholar 

  53. Bedford MT, Frankel A, Yaffe MB et al. Arginine methylation inhibits the binding of proline-rich ligands to Src homology 3, but not WW, domains. J Biol Chem 2000; 275:16030–16036.

    Article  CAS  PubMed  Google Scholar 

  54. Côté J, Boisvert FM, Boulanger MC et al. Sam68 RNA binding protein is an in vivo substrate for protein arginine N-methyltransferase. Mol Biol Cell 2003; 14:274–287.

    Article  PubMed  Google Scholar 

  55. Polotskaia A, Wang M, Patschan S et al. Regulation of arginine methylation in endothelial cells: role in premature senescence and apoptosis. Cell Cycle 2007; 6:2524–2530.

    Article  CAS  PubMed  Google Scholar 

  56. Rho J, Choi S, Jung CR et al. Arginine methylation of Sam68 and SLM proteins negatively regulates their poly(U) RNA binding activity. Arch Biochem Biophys 2007; 466:49–57.

    Article  CAS  PubMed  Google Scholar 

  57. Cheung N, Chan LC, Thompson A et al. Protein arginine-methyltransferase-dependent oncogenesis. Nat Cell Biol 2007; 9:1208–1215.

    Article  CAS  PubMed  Google Scholar 

  58. Babic I, Jakymiw A, Fujita DJ. The RNA binding protein Sam68 is acetylated in tumor cell lines and its acetylation correlates with enhanced RNA binding activity. Oncogene 2004; 23:3781–3789.

    Article  CAS  PubMed  Google Scholar 

  59. Babic I, Cherry E, Fujita DJ. SUMO modification of Sam68 enhances its ability to repress cyclin D1 expression and inhibits its ability to induce apoptosis. Oncogene 2006; 25:4955–4964.

    Article  CAS  PubMed  Google Scholar 

  60. Di Fruscio M, Chen T, Richard S. Characterization of Sam68-like mammalian proteins SLM-1 and SLM-2: SLM-1 is a Src substrate during mitosis. Proc Natl Acad Sci USA 1999; 96:2710–2715.

    Article  PubMed  Google Scholar 

  61. Venables JP, Vernet C, Chew SL et al. T-STAR/ETOILE: a novel relative of SAM68 that interacts with an RNA-binding protein implicated in spermatogenesis. Hum Mol Genet 1999; 8:959–969.

    Article  CAS  PubMed  Google Scholar 

  62. Reddy TR, Suhasini M, Xu W et al. A role for KH domain proteins (Sam68-like mammalian proteins and quaking proteins) in the post-transcriptional regulation of HIV replication. J Biol Chem 2002; 277:5778–5784.

    Article  CAS  PubMed  Google Scholar 

  63. Stoss O, Olbrich M, Hartmann AM et al. The STAR/GSG family protein rSLM-2 regulates the selection of alternative splice sites. J Biol Chem 2001; 276:8665–8673.

    Article  CAS  PubMed  Google Scholar 

  64. Richard S, Torabi N, Franco GV et al. Ablation of the Sam68 RNA binding protein protects mice from age-related bone loss. PLoS Genet 2005; 1(6):e74.

    Article  PubMed  Google Scholar 

  65. Ebersole TA, Chen Q, Justice MJ et al. The quaking gene product necessary in embryogenesis and myelination combines features of RNA binding and signal transduction proteins. Nat Genet 1996; 12:260–265.

    Article  CAS  PubMed  Google Scholar 

  66. Hardy RJ, Loushin CL, Friedrich VL Jr et al. Neural cell type-specific expression of QKI proteins is altered in quakingviable mutant mice. J Neurosci 1996; 16:7941–7949.

    CAS  PubMed  Google Scholar 

  67. Wu J, Zhou L, Tonissen K et al. The quaking I-5 protein (QKI-5) has a novel nuclear localization signal and shuttles between the nucleus and the cytoplasm. J Biol Chem 1999; 274:29202–29210.

    Article  CAS  PubMed  Google Scholar 

  68. Chen T, Richard S. Structure-function analysis of Qk1: a lethal point mutation in mouse quaking prevents homodimerization. Mol Cell Biol 1998; 18:4863–4871.

    CAS  PubMed  Google Scholar 

  69. Wu JI, Reed RB, Grabowski PJ et al. Function of quaking in myelination: regulation of alternative splicing. Proc Natl Acad Sci USA 2002; 99:4233–4238.

    Article  CAS  PubMed  Google Scholar 

  70. Li Z, Zhang Y, Li D et al. Destabilization and mislocalization of myelin basic protein mRNAs in quaking dysmyelination lacking the QKI RNA-binding proteins. J Neurosci 2000; 20:4944–4953.

    CAS  PubMed  Google Scholar 

  71. Larocque D, Pilotte J, Chen T et al. Nuclear retention of MBP mRNAs in the quaking viable mice. Neuron 2002; 36:815–829.

    Article  CAS  PubMed  Google Scholar 

  72. Zhang Y, Lu Z, Ku L et al. Tyrosine phosphorylation of QKI mediates developmental signals to regulate mRNA metabolism. EMBO J 2003; 22:1801–1810.

    Article  CAS  PubMed  Google Scholar 

  73. Lu Z, Ku L, Chen Y et al. Developmental abnormalities of myelin basic protein expression in fyn knock-out brain reveal a role of Fyn in post-transcriptional regulation. J Biol Chem 2005; 280:389–395.

    CAS  PubMed  Google Scholar 

  74. Krämer A. Purification of splicing factor SF1, a heat-stable protein that functions in the assembly of a presplicing complex. Mol Cell Biol 1992; 12:4545–4552.

    PubMed  Google Scholar 

  75. Liu Z, Luyten I, Bottomley MJ et al. Structural basis for recognition of the intron branch site RNA by splicing factor 1. Science 2001; 294:1098–1102.

    Article  CAS  PubMed  Google Scholar 

  76. Lin KT, Lu RM, Tarn WY. The WW domain-containing proteins interact with the early spliceosome and participate in pre-mRNA splicing in vivo. Mol Cell Biol 2004; 24:9176–9185.

    Article  CAS  PubMed  Google Scholar 

  77. Berglund JA, Abovich N, Rosbash M. A cooperative interaction between U2AF65 and mBBP/SF1 facilitates branchpoint region recognition. Genes Dev 1998; 12:858–867.

    Article  CAS  PubMed  Google Scholar 

  78. Wang X, Bruderer S, Rafi Z et al. Phosphorylation of splicing factor SF1 on Ser20 by cGMP-dependent protein kinase regulates spliceosome assembly. EMBO J 1999; 18:4549–4559.

    Article  CAS  PubMed  Google Scholar 

  79. Manceau V, Swenson M, Le Caer JP et al. Major phosphorylation of SF1 on adjacent Ser-Pro motifs enhances interaction with U2AF65. FEBS J 2006; 273:577–587.

    Article  CAS  PubMed  Google Scholar 

  80. Nabel-Rosen H, Dorevitch N, Reuveny A et al. The balance between two isoforms of the Drosophila RNA-binding protein how controls tendon cell differentiation. Mol Cell 1999; 4:573–584.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Public Health and Cell Biology, University of Rome “Tor Vergata”, Via Montpellier, 1, 00133, Rome, Italy

    Claudio Sette

Authors
  1. Claudio Sette
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Claudio Sette .

Editor information

Editors and Affiliations

  1. Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel

    Talila Volk BSc, MSc, PhD

  2. Department of Molecular Genetics and Microbiology, Institute of Cell and Molecular Biology, University of Texas at Austin, Austin, Texas, USA

    Karen Artzt BA, PhD

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Landes Bioscience and Springer Science+Business Media

About this chapter

Cite this chapter

Sette, C. (2010). Post-translational Regulation of STAR Proteins and Effects on Their Biological Functions. In: Volk, T., Artzt, K. (eds) Post-Transcriptional Regulation by STAR Proteins. Advances in Experimental Medicine and Biology, vol 693. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-7005-3_4

Download citation

Publish with us

Policies and ethics

Search

Navigation