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词条 KHDRBS1
释义

  1. Function

  2. Gene knockout studies

  3. References

  4. Further reading

{{Infobox_gene}}KH domain-containing, RNA-binding, signal transduction-associated protein 1 is a protein that in humans is encoded by the KHDRBS1 gene.[1][2]

This gene encodes a member of the K homology domain-containing, RNA-binding, signal transduction-associated protein family. The encoded protein appears to have many functions and may be involved in a variety of cellular processes, including alternative splicing, cell cycle regulation, RNA 3'-end formation, tumorigenesis, and regulation of human immunodeficiency virus gene expression.[3]

Function

Sam68 (the Src-Associated substrate in Mitosis of 68 kDa) is officially called KHDRBS1 (KH domain containing, RNA binding, signal transduction associated 1). Sam68 is a KH-type RNA binding protein that recognizes U(U/A)AA direct repeats with relative high affinity.[4][5] Sam68 is predominantly nuclear and its major function in the nucleus is to regulate alternative splicing by recognizing RNA sequences neighboring the included/excluded exon(s). Direct evidence for the involvement of Sam68 in alternative splicing has been shown in promoting the inclusion of the variable exon 5 (v5) in CD44 correlating with cell migration potential.[6][7] In addition, Sam68 in conjunction with hnRNPA1 influences the choice of the alternative 5' splice sites of Bcl-x regulating pro-survival and apoptotic pathways.[8] The role of Sam68 was further highlighted in spinal muscular atrophy (SMA), as Sam68 promotes the skipping of exon 7 leading to a non-functional SMN2 protein.[9] Sam68 was demonstrated to be involved in the alternative splicing of mRNAs implicated in normal neurogenesis using splicing-sensitive microarrays.[10] Sam68 was also shown to participate in the epithelial-to-mesenchymal transition by regulating the alternative splicing of SF2/ASF.[9] Sam68 was shown to regulate the activity-dependent alternative splicing of the neurexin-1 in the central nervous system with implications for neurodevelopment disorders.[11] Sam68 influences alternative splicing of the mTOR kinase contributing to the lean phenotype observed in the Sam68 deficient mice.[12]

The RNA binding activity of Sam68 is regulated by post-translational modifications such that Sam68 is often referred to as a STAR (Signal Transduction Activator of RNA) protein by which signals from growth factors or soluble tyrosine kinases, such as Src family kinases, act to regulate cellular RNA processes such as alternative splicing.[13] For example, the Sam68-dependent CD44 alternative splicing of exon v5 is regulated by ERK phosphorylation of Sam68[7] and Bcl-x alternative splicing is regulated by the p59fyn-dependent phosphorylation of Sam68.[8] Sam68 is also downstream of the epidermal growth factor receptor (EGFR),[14] hepatocyte growth factor (HGF)/Met receptor (c-Met),[15] leptin[16] and tumor necrosis factor (TNF) receptors.[17] While the role of Sam68 in these pathways is slowly emerging much remains to be determined. Sam68 has also been shown to re-localize in the cytoplasm near the plasma membrane, where it functions to transport and regulate the translation of certain mRNAs[18] and regulates cell migration.[14]

Gene knockout studies

Sam68-deficient mice were generated by targeted disruption of exons 4-5 of the sam68 gene, which encode the functional region of the KH domain.[19] The genotypes of the offspring from heterozygote intercrosses exhibited a Mendelian segregation at E18.5. Despite the lack of visible deformity, many of the Sam68-/- pups died at birth of unknown causes.[19] Sam68+/- mice were phenotypically normal and Sam68-/- pups that survived the peri-natal period invariably lived to old age. Sam68-/- mice weighed less than Sam68+/+ littermates and magnetic resonance imaging analysis confirmed that young Sam68-/- mice exhibited a profound reduction in adiposity, although food intake was similar.[12] Moreover, Sam68-/- mice were protected against dietary-induced obesity.[12] Sam68 deficient preadipocytes (3T3-L1 cells) had impaired adipogenesis and Sam68-/- mice had ~45% less adult derived stem cells (ADSCs) in their stromal vascular fraction (SVF) from WAT.[12]

Sam68-/- mice did not develop tumors and showed no immunological or other major illnesses. Sam68-/- mice did, however, have difficulty breeding due to male infertility[18][19] and female subfertility.[20] The Sam68-null mice exhibited motor coordination defects and fell from the rotating drum at lower speeds and prematurely compared to the wild-type controls.[21] Sam68-/- mice are protected against age-induced osteoporosis.[19] Using the mammary tumor virus-polyoma middle T-antigen (MMTV-PyMT) mouse model of mammary tumorigenesis, it was shown that reduced Sam68 expression decreases tumor burden and metastasis.[22] Kaplan-Meier curves showed that loss of one sam68 allele (PyMT; Sam68+/-) was associated with a significant delay in the onset of palpable tumors and a significant reduction in tumor multiplicity. These findings suggest that Sam68 is required for PyMT-induced mammary tumorigenesis. The knockdown of Sam68 expression in PyMT-derived mammary cells reduced the number of lung tumor foci in athymic mice, suggesting that Sam68 is also required for mammary tumor metastasis. The knockdown of Sam68 delayed LNCaP prostate cancer cells proliferation.[23] The roles of Sam68 in cancer have been reviewed.[24]

References

1. ^{{cite journal |vauthors=Wong G, Muller O, Clark R, Conroy L, Moran MF, Polakis P, McCormick F | title = Molecular cloning and nucleic acid binding properties of the GAP-associated tyrosine phosphoprotein p62 | journal = Cell | volume = 69 | issue = 3 | pages = 551–8 |date=Jun 1992 | pmid = 1374686 | pmc = | doi =10.1016/0092-8674(92)90455-L }}
2. ^{{cite journal |vauthors=Lee J, Burr JG | title = Salpalpha and Salpbeta, growth-arresting homologs of Sam68 | journal = Gene | volume = 240 | issue = 1 | pages = 133–47 |date=Jan 2000 | pmid = 10564820 | pmc = | doi =10.1016/S0378-1119(99)00421-7 }}
3. ^{{cite web | title = Entrez Gene: KH domain containing, RNA binding, signal transduction associated 1 | url = https://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=retrieve&list_uids=10657}}
4. ^{{cite journal |vauthors=Galarneau A, Richard S | title = The STAR RNA binding proteins GLD-1, QKI, SAM68 and SLM-2 bind bipartite RNA motifs | journal = BMC Mol Biol | volume = 10 | issue = 47 | pages = 47|date=May 2009 | pmid = 19457263 | pmc = 2697983| doi =10.1186/1471-2199-10-47 }}
5. ^{{cite journal |vauthors=Lin Q, Taylor SJ, Shalloway D | title = Specificity and determinants of Sam68 RNA binding. Implications for the biological function of K homology domains | journal = J Biol Chem | volume = 272 | issue = 43 | pages = 27274–27280 |date=Oct 1997 | pmid = 9341174 | pmc = | doi = 10.1074/jbc.272.43.27274}}
6. ^{{cite journal |vauthors=Cheng C, Sharp PA | title = Regulation of CD44 alternative splicing by SRm160 and its potential role in tumor cell invasion | journal = Mol Cell Biol | volume = 26 | issue = 1 | pages = 362–70 |date=Jan 2006 | pmid = 16354706 | pmc = 1317625| doi = 10.1128/MCB.26.1.362-370.2006}}
7. ^1 {{cite journal |vauthors=Matter N, Herrlich P, Konig H | title = Signal-dependent regulation of splicing via phosphorylation of Sam68 | journal = Nature | volume = 420 | issue = 6916 | pages = 691–5 |date=Dec 2002 | pmid = 12478298 | pmc = | doi = 10.1038/nature01153}}
8. ^1 {{cite journal |vauthors=Paronetto MP, Achsel T, Massiello A, Chalfant CE, Sette C | title = The RNA-binding protein Sam68 modulates the alternative splicing of Bcl-x | journal = J Cell Biol | volume = 176 | issue = 7 | pages= 929–39 |date=Mar 2007 | pmid = 17371836 | pmc = 2064079| doi = 10.1083/jcb.200701005}}
9. ^1 {{cite journal |vauthors=Pedrotti S, Bielli P, Paronetto MP, Ciccosanti F, Fimia GM, Stamm S, Manley JL, Sette C | title = The splicing regulator Sam68 binds to a novel exonic splicing silencer and functions in SMN2 alternative splicing in spinal muscular atrophy | journal = EMBO J | volume = 29 | issue = 7 | pages = 1235–47 |date=Apr 2010 | pmid = 20186123 | pmc = 2857462| doi =10.1038/emboj.2010.19 }}
10. ^{{cite journal |vauthors=Chawla G, Lin CH, Han A, Shiue L, Ares MJ, Black DL | title = Sam68 regulates a set of alternatively spliced exons during neurogenesis | journal = Mol Cell Biol | volume = 29 | issue = 1 | pages = 201–13 |date=Jan 2009 | pmid = 18936165 | pmc = 2612485| doi =10.1128/MCB.01349-08 }}
11. ^{{cite journal |vauthors=Iijima T, Wu K, Witte H, Hanno-Iijima Y, Glatter T, Richard S, Scheiffele P | title = SAM68 regulates neuronal activity-dependent alternative splicing of neurexin-1 | journal = Cell | volume = 147 | issue = 7 | pages = 1601–14 |date=Dec 2011 | pmid = 22196734 | pmc = 3246220| doi =10.1016/j.cell.2011.11.028 }}
12. ^1 2 3 {{cite journal |vauthors=Huot ME, Vogel G, Zabarauskas A, Ngo CT, Coulombe-Huntington J, Majewski J, Richard S | title = The Sam68 STAR RNA-binding protein regulates mTOR alternative splicing during adipogenesis | journal = Mol Cell | volume = 46 | issue = 2 | pages = 187–99 |date=Apr 2012 | pmid = 22424772 | pmc = | doi =10.1016/j.molcel.2012.02.007 }}
13. ^{{cite book | author = Richard S | title = Reaching for the stars: Linking RNA binding proteins to diseases | journal = Adv Exp Med Biol | volume = 693 | issue = | pages = 142–57 | year = 2010 | month = | pmid = 21189691 | pmc = | doi = 10.1007/978-1-4419-7005-3_10| series = Advances in Experimental Medicine and Biology | isbn = 978-1-4419-7004-6 }}
14. ^1 {{cite journal |vauthors=Huot ME, Vogel G, Richard S | title = Identification of a Sam68 ribonucleoprotein complex regulated by epidermal growth factor | journal = J Biol Chem | volume = 284 | issue = 46 | pages = 31903–13 |date=Nov 2009 | pmid = 19762470 | pmc = 2797261| doi =10.1074/jbc.M109.018465 }}
15. ^{{cite journal |vauthors=Locatelli A, Lange CA | title = Met receptors induce Sam68-dependent cell migration by activation of alternate extracellular signal-regulated kinase family members | journal = J Biol Chem | volume = 286 | issue = 24 | pages = 21062–72 |date=Jun 2011 | pmid = 21489997 | pmc = 3122167| doi =10.1074/jbc.M110.211409 }}
16. ^{{cite journal |vauthors=Maroni P, Citterio L, Piccoletti R, Bendinelli P | title = Sam68 and ERKs regulate leptin-induced expression of OB-Rb mRNA in C2C12 myotubes | journal = Mol Cell Endocrinol | volume = 309 | issue = 1–2 | pages = 26–31 |date=Oct 2009 | pmid = 19524014 | pmc = | doi =10.1016/j.mce.2009.05.021 }}
17. ^{{cite journal |vauthors=Ramakrishnan P, Baltimore D | title = Sam68 is required for both NF-κB activation and apoptosis signaling by the TNF receptor | journal = Mol Cell | volume = 43 | issue = 2 | pages = 167–79 |date=Jul 2011 | pmid = 21620750 | pmc = 3142289| doi =10.1016/j.molcel.2011.05.007 }}
18. ^1 {{cite journal |vauthors=Paronetto MP, Messina V, Bianchi E, Barchi M, Vogel G, Moretti C, Palombi F, Stefanini M, Geremia R, Richard S, Sette C | title = Sam68 regulates translation of target mRNAs in male germ cells, necessary for mouse spermatogenesis | journal = J Cell Biol | volume = 185 | issue = 2 | pages = 235–49 |date=Apr 2009 | pmid = 19380878 | pmc = 2700383| doi =10.1083/jcb.200811138 }}
19. ^1 2 3 {{cite journal |vauthors=Richard S, Torabi N, Franco GV, Tremblay GA, Chen T, Vogel G, Morel M, Cleroux P, Forget-Richard A, Komarova S, Tremblay ML, Li W, Li A, Gao YJ, Henderson JE | title = Ablation of the Sam68 RNA binding protein protects mice from age-related bone loss | journal = PLoS Genet | volume = 1 | issue = 6 | pages = e74 |date=Dec 2005 | pmid = 16362077 | pmc = 1315279| doi = 10.1371/journal.pgen.0010074}}
20. ^{{cite journal |vauthors=Bianchi E, Barbagallo F, Valeri C, Geremia R, Salustri A, De Felici M, Sette C | title = Ablation of the Sam68 gene impairs female fertility and gonadotropin-dependent follicle development | journal = Hum Mol Genet | volume = 19 | issue = 24 | pages = 4886–94 |date=Dec 2010 | pmid = 20881015 | pmc = | doi =10.1093/hmg/ddq422 }}
21. ^{{cite journal |vauthors=Lukong KE, Richard S | title = Motor coordination defects in mice deficient for the Sam68 RNA-binding protein | journal = Behav Brain Res | volume = 189 | issue = 2 | pages = 357–63 |date=Jun 2008 | pmid = 18325609 | pmc = | doi =10.1016/j.bbr.2008.01.010 }}
22. ^{{cite journal |vauthors=Richard S, Vogel G, Huot ME, Guo T, Muller WJ, Lukong KE | title = Sam68 haploinsufficiency delays onset of mammary tumorigenesis and metastasis | journal = Oncogene | volume = 27 | issue = 4 | pages = 548–56 |date=Jan 2008 | pmid = 17621265 | pmc = | doi = 10.1038/sj.onc.1210652}}
23. ^{{cite journal |vauthors=Busà R, Paronetto MP, Farini D, Pierantozzi E, Botti F, Angelini DF, Attisani F, Vespasiani G, Sette C | title = The RNA-binding protein Sam68 contributes to proliferation and survival of human prostate cancer cells | journal = Oncogene | volume = 26 | issue = 30 | pages = 4372–82 |date=Jun 2007 | pmid = 17237817 | pmc = | doi = 10.1038/sj.onc.1210224}}
24. ^{{cite journal |vauthors=Bielli P, Busà R, Paronetto MP, Sette C | title = The RNA-binding protein Sam68 is a multifunctional player in human cancer | journal = Endocr Relat Cancer | volume = 18 | issue = 4 | pages = R91–R102 |date=Jul 2011 | pmid = 21565971 | pmc = | doi =10.1530/ERC-11-0041 }}

Further reading

{{refbegin|35em}}
  • {{cite journal |vauthors=Najib S, Martín-Romero C, González-Yanes C, Sánchez-Margalet V |title=Role of Sam68 as an adaptor protein in signal transduction. |journal=Cell. Mol. Life Sci. |volume=62 |issue= 1 |pages= 36–43 |year= 2005 |pmid= 15619005 |doi= 10.1007/s00018-004-4309-3 }}
  • {{cite journal |vauthors=Koch CA, Moran MF, Anderson D, etal |title=Multiple SH2-mediated interactions in v-src-transformed cells. |journal=Mol. Cell. Biol. |volume=12 |issue= 3 |pages= 1366–74 |year= 1992 |pmid= 1545818 |doi= 10.1128/mcb.12.3.1366| pmc=369570 }}
  • {{cite journal |vauthors=Weng Z, Thomas SM, Rickles RJ, etal |title=Identification of Src, Fyn, and Lyn SH3-binding proteins: implications for a function of SH3 domains. |journal=Mol. Cell. Biol. |volume=14 |issue= 7 |pages= 4509–21 |year= 1994 |pmid= 7516469 |doi= 10.1128/MCB.14.7.4509| pmc=358823 }}
  • {{cite journal |vauthors=Taylor SJ, Anafi M, Pawson T, Shalloway D |title=Functional interaction between c-Src and its mitotic target, Sam 68. |journal=J. Biol. Chem. |volume=270 |issue= 17 |pages= 10120–4 |year= 1995 |pmid= 7537265 |doi=10.1074/jbc.270.17.10120 }}
  • {{cite journal |vauthors=Richard S, Yu D, Blumer KJ, etal |title=Association of p62, a multifunctional SH2- and SH3-domain-binding protein, with src family tyrosine kinases, Grb2, and phospholipase C gamma-1. |journal=Mol. Cell. Biol. |volume=15 |issue= 1 |pages= 186–97 |year= 1995 |pmid= 7799925 |doi= 10.1128/MCB.15.1.186| pmc=231932 }}
  • {{cite journal |vauthors=Nunès JA, Truneh A, Olive D, Cantrell DA |title=Signal transduction by CD28 costimulatory receptor on T cells. B7-1 and B7-2 regulation of tyrosine kinase adaptor molecules. |journal=J. Biol. Chem. |volume=271 |issue= 3 |pages= 1591–8 |year= 1996 |pmid= 8576157 |doi=10.1074/jbc.271.3.1591 }}
  • {{cite journal |vauthors=Vadlamudi RK, Joung I, Strominger JL, Shin J |title=p62, a phosphotyrosine-independent ligand of the SH2 domain of p56lck, belongs to a new class of ubiquitin-binding proteins. |journal=J. Biol. Chem. |volume=271 |issue= 34 |pages= 20235–7 |year= 1996 |pmid= 8702753 |doi=10.1074/jbc.271.34.20235 }}
  • {{cite journal |vauthors=Finan PM, Hall A, Kellie S |title=Sam68 from an immortalised B-cell line associates with a subset of SH3 domains. |journal=FEBS Lett. |volume=389 |issue= 2 |pages= 141–4 |year= 1996 |pmid= 8766817 |doi=10.1016/0014-5793(96)00552-2 }}
  • {{cite journal |vauthors=Bunnell SC, Henry PA, Kolluri R, etal |title=Identification of Itk/Tsk Src homology 3 domain ligands. |journal=J. Biol. Chem. |volume=271 |issue= 41 |pages= 25646–56 |year= 1996 |pmid= 8810341 |doi=10.1074/jbc.271.41.25646 }}
  • {{cite journal |vauthors=Andreotti AH, Bunnell SC, Feng S, etal |title=Regulatory intramolecular association in a tyrosine kinase of the Tec family. |journal=Nature |volume=385 |issue= 6611 |pages= 93–7 |year= 1997 |pmid= 8985255 |doi= 10.1038/385093a0 }}
  • {{cite journal |vauthors=Trüb T, Frantz JD, Miyazaki M, etal |title=The role of a lymphoid-restricted, Grb2-like SH3-SH2-SH3 protein in T cell receptor signaling. |journal=J. Biol. Chem. |volume=272 |issue= 2 |pages= 894–902 |year= 1997 |pmid= 8995379 |doi=10.1074/jbc.272.2.894 }}
  • {{cite journal |vauthors=Lawe DC, Hahn C, Wong AJ |title=The Nck SH2/SH3 adaptor protein is present in the nucleus and associates with the nuclear protein SAM68. |journal=Oncogene |volume=14 |issue= 2 |pages= 223–31 |year= 1997 |pmid= 9010224 |doi= 10.1038/sj.onc.1200821 }}
  • {{cite journal |vauthors=Barlat I, Maurier F, Duchesne M, etal |title=A role for Sam68 in cell cycle progression antagonized by a spliced variant within the KH domain. |journal=J. Biol. Chem. |volume=272 |issue= 6 |pages= 3129–32 |year= 1997 |pmid= 9013542 |doi=10.1074/jbc.272.6.3129 }}
  • {{cite journal |vauthors=Fusaki N, Iwamatsu A, Iwashima M, Fujisawa J |title=Interaction between Sam68 and Src family tyrosine kinases, Fyn and Lck, in T cell receptor signaling. |journal=J. Biol. Chem. |volume=272 |issue= 10 |pages= 6214–9 |year= 1997 |pmid= 9045636 |doi=10.1074/jbc.272.10.6214 }}
  • {{cite journal |vauthors=Guinamard R, Fougereau M, Seckinger P |title=The SH3 domain of Bruton's tyrosine kinase interacts with Vav, Sam68 and EWS. |journal=Scand. J. Immunol. |volume=45 |issue= 6 |pages= 587–95 |year= 1997 |pmid= 9201297 |doi=10.1046/j.1365-3083.1997.d01-447.x }}
  • {{cite journal |vauthors=Resnick RJ, Taylor SJ, Lin Q, Shalloway D |title=Phosphorylation of the Src substrate Sam68 by Cdc2 during mitosis. |journal=Oncogene |volume=15 |issue= 11 |pages= 1247–53 |year= 1997 |pmid= 9315091 |doi= 10.1038/sj.onc.1201289 }}
  • {{cite journal |vauthors=Chen T, Damaj BB, Herrera C, etal |title=Self-association of the single-KH-domain family members Sam68, GRP33, GLD-1, and Qk1: role of the KH domain. |journal=Mol. Cell. Biol. |volume=17 |issue= 10 |pages= 5707–18 |year= 1997 |pmid= 9315629 |doi= 10.1128/MCB.17.10.5707| pmc=232419 }}
  • {{cite journal |vauthors=Tang J, Feng GS, Li W |title=Induced direct binding of the adapter protein Nck to the GTPase-activating protein-associated protein p62 by epidermal growth factor. |journal=Oncogene |volume=15 |issue= 15 |pages= 1823–32 |year= 1997 |pmid= 9362449 |doi= 10.1038/sj.onc.1201351 }}
  • {{cite journal |vauthors=Sung CK, Choi WS, Sanchez-Margalet V |title=Guanosine triphosphatase-activating protein-associated protein, but not src-associated protein p68 in mitosis, is a part of insulin signaling complexes. |journal=Endocrinology |volume=139 |issue= 5 |pages= 2392–8 |year= 1998 |pmid= 9564850 |doi=10.1210/en.139.5.2392 }}
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