KHDRBS1

KH domain-containing, RNA-binding, signal transduction-associated protein 1 is a protein that in humans is encoded by the KHDRBS1 gene.[5][6]

KHDRBS1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesKHDRBS1, Sam68, p62, p68, KH domain containing, RNA binding, signal transduction associated 1, KH RNA binding domain containing, signal transduction associated 1
External IDsOMIM: 602489 MGI: 893579 HomoloGene: 4781 GeneCards: KHDRBS1
Orthologs
SpeciesHumanMouse
Entrez

10657

20218

Ensembl

ENSG00000121774

ENSMUSG00000028790

UniProt

Q07666

Q60749

RefSeq (mRNA)

NM_001271878
NM_006559

NM_011317

RefSeq (protein)

NP_001258807
NP_006550

NP_035447

Location (UCSC)Chr 1: 32.01 – 32.06 MbChr 4: 129.6 – 129.64 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[7]

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.[8][9] 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).

Clinical significance

Sam68 influences the alternative splicing of a number of genes central to processes such as neurogenesis and adipogenesis as well as diseases such as spinal muscular atrophy (SMA) and cancer.

Neurogenesis

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.[11] Sam68 was shown to regulate the activity-dependent alternative splicing of the neurexin-1 in the central nervous system with implications for neurodevelopment disorders.[12]

Adipogenesis

Sam68 influences alternative splicing of the mTOR kinase contributing to the lean phenotype observed in the Sam68 deficient mice.[13]

Spinal muscular atrophy

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.[11]

Cancer

Sam68 regulates the alternative splicing of a number of cancer-related genes.

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.[14][15] CD44 is a cell surface protein whose expression has been linked to cancer, with its expression predicting prognosis in a number of tumour types.[16][17] In prostate cancer, Sam68 also interacts with splicing complex proteins KHDRBS3 (T-STAR) and Metadherin (MTDH) which also alter CD44 splicing.[17] Subsequently, the knockdown of Sam68 has been shown to delay LNCaP prostate cancer cells proliferation.[18]

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.[19]

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.[20] For example, the Sam68-dependent CD44 alternative splicing of exon v5 is regulated by ERK phosphorylation of Sam68[15] and Bcl-x alternative splicing is regulated by the p59fyn-dependent phosphorylation of Sam68.[19]

Sam68 is also downstream of the epidermal growth factor receptor (EGFR),[21] hepatocyte growth factor (HGF)/Met receptor (c-Met),[22] leptin[23] and tumor necrosis factor (TNF) receptors.[24] 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[25] and regulates cell migration.[21]

The many roles of Sam68 in cancer have been reviewed by Bielli et al.,.[26]

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.[27] 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.[27] 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.[13] Moreover, Sam68-/- mice were protected against dietary-induced obesity.[13] 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.[13]

Tumour formation in vivo

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[25][27] and female subfertility.[28] 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.[29] Sam68-/- mice are protected against age-induced osteoporosis.[27] 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.[30] 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.

References
  1. GRCh38: Ensembl release 89: ENSG00000121774 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000028790 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Wong G, Muller O, Clark R, Conroy L, Moran MF, Polakis P, McCormick F (Jun 1992). "Molecular cloning and nucleic acid binding properties of the GAP-associated tyrosine phosphoprotein p62". Cell. 69 (3): 551–8. doi:10.1016/0092-8674(92)90455-L. PMID 1374686. S2CID 30950990.
  6. Lee J, Burr JG (Jan 2000). "Salpalpha and Salpbeta, growth-arresting homologs of Sam68". Gene. 240 (1): 133–47. doi:10.1016/S0378-1119(99)00421-7. PMID 10564820.
  7. "Entrez Gene: KH domain containing, RNA binding, signal transduction associated 1".
  8. Galarneau A, Richard S (May 2009). "The STAR RNA binding proteins GLD-1, QKI, SAM68 and SLM-2 bind bipartite RNA motifs". BMC Mol Biol. 10 (47): 47. doi:10.1186/1471-2199-10-47. PMC 2697983. PMID 19457263.
  9. Lin Q, Taylor SJ, Shalloway D (Oct 1997). "Specificity and determinants of Sam68 RNA binding. Implications for the biological function of K homology domains". J Biol Chem. 272 (43): 27274–27280. doi:10.1074/jbc.272.43.27274. PMID 9341174.
  10. Chawla G, Lin CH, Han A, Shiue L, Ares MJ, Black DL (Jan 2009). "Sam68 regulates a set of alternatively spliced exons during neurogenesis". Mol Cell Biol. 29 (1): 201–13. doi:10.1128/MCB.01349-08. PMC 2612485. PMID 18936165.
  11. Pedrotti S, Bielli P, Paronetto MP, Ciccosanti F, Fimia GM, Stamm S, Manley JL, Sette C (Apr 2010). "The splicing regulator Sam68 binds to a novel exonic splicing silencer and functions in SMN2 alternative splicing in spinal muscular atrophy". EMBO J. 29 (7): 1235–47. doi:10.1038/emboj.2010.19. PMC 2857462. PMID 20186123.
  12. Iijima T, Wu K, Witte H, Hanno-Iijima Y, Glatter T, Richard S, Scheiffele P (Dec 2011). "SAM68 regulates neuronal activity-dependent alternative splicing of neurexin-1". Cell. 147 (7): 1601–14. doi:10.1016/j.cell.2011.11.028. PMC 3246220. PMID 22196734.
  13. Huot ME, Vogel G, Zabarauskas A, Ngo CT, Coulombe-Huntington J, Majewski J, Richard S (Apr 2012). "The Sam68 STAR RNA-binding protein regulates mTOR alternative splicing during adipogenesis". Mol Cell. 46 (2): 187–99. doi:10.1016/j.molcel.2012.02.007. PMID 22424772.
  14. Cheng C, Sharp PA (Jan 2006). "Regulation of CD44 alternative splicing by SRm160 and its potential role in tumor cell invasion". Mol Cell Biol. 26 (1): 362–70. doi:10.1128/MCB.26.1.362-370.2006. PMC 1317625. PMID 16354706.
  15. Matter N, Herrlich P, Konig H (Dec 2002). "Signal-dependent regulation of splicing via phosphorylation of Sam68". Nature. 420 (6916): 691–5. Bibcode:2002Natur.420..691M. doi:10.1038/nature01153. PMID 12478298. S2CID 4349060.
  16. Naor, David; Nedvetzki, Shlomo; Golan, Itshak; Melnik, Lora; Faitelson, Yoram (November 2002). "CD44 in cancer". Critical Reviews in Clinical Laboratory Sciences. 39 (6): 527–579. doi:10.1080/10408360290795574. ISSN 1040-8363. PMID 12484499. S2CID 30019668.
  17. Luxton, Hayley J.; Simpson, Benjamin S.; Mills, Ian G.; Brindle, Nicola R.; Ahmed, Zeba; Stavrinides, Vasilis; Heavey, Susan; Stamm, Stefan; Whitaker, Hayley C. (2019-08-23). "The Oncogene Metadherin Interacts with the Known Splicing Proteins YTHDC1, Sam68 and T-STAR and Plays a Novel Role in Alternative mRNA Splicing". Cancers. 11 (9): 1233. doi:10.3390/cancers11091233. ISSN 2072-6694. PMC 6770463. PMID 31450747.
  18. Busà R, Paronetto MP, Farini D, Pierantozzi E, Botti F, Angelini DF, Attisani F, Vespasiani G, Sette C (Jun 2007). "The RNA-binding protein Sam68 contributes to proliferation and survival of human prostate cancer cells". Oncogene. 26 (30): 4372–82. doi:10.1038/sj.onc.1210224. PMID 17237817.
  19. Paronetto MP, Achsel T, Massiello A, Chalfant CE, Sette C (Mar 2007). "The RNA-binding protein Sam68 modulates the alternative splicing of Bcl-x". J Cell Biol. 176 (7): 929–39. doi:10.1083/jcb.200701005. PMC 2064079. PMID 17371836.
  20. Richard S (2010). "Reaching for the STARs: Linking RNA Binding Proteins to Diseases". Post-Transcriptional Regulation by STAR Proteins. Advances in Experimental Medicine and Biology. Vol. 693. pp. 142–57. doi:10.1007/978-1-4419-7005-3_10. ISBN 978-1-4419-7004-6. PMID 21189691.
  21. Huot ME, Vogel G, Richard S (Nov 2009). "Identification of a Sam68 ribonucleoprotein complex regulated by epidermal growth factor". J Biol Chem. 284 (46): 31903–13. doi:10.1074/jbc.M109.018465. PMC 2797261. PMID 19762470.
  22. Locatelli A, Lange CA (Jun 2011). "Met receptors induce Sam68-dependent cell migration by activation of alternate extracellular signal-regulated kinase family members". J Biol Chem. 286 (24): 21062–72. doi:10.1074/jbc.M110.211409. PMC 3122167. PMID 21489997.
  23. Maroni P, Citterio L, Piccoletti R, Bendinelli P (Oct 2009). "Sam68 and ERKs regulate leptin-induced expression of OB-Rb mRNA in C2C12 myotubes" (PDF). Mol Cell Endocrinol. 309 (1–2): 26–31. doi:10.1016/j.mce.2009.05.021. PMID 19524014. S2CID 28228732.
  24. Ramakrishnan P, Baltimore D (Jul 2011). "Sam68 is required for both NF-κB activation and apoptosis signaling by the TNF receptor". Mol Cell. 43 (2): 167–79. doi:10.1016/j.molcel.2011.05.007. PMC 3142289. PMID 21620750.
  25. Paronetto MP, Messina V, Bianchi E, Barchi M, Vogel G, Moretti C, Palombi F, Stefanini M, Geremia R, Richard S, Sette C (Apr 2009). "Sam68 regulates translation of target mRNAs in male germ cells, necessary for mouse spermatogenesis". J Cell Biol. 185 (2): 235–49. doi:10.1083/jcb.200811138. PMC 2700383. PMID 19380878.
  26. Bielli P, Busà R, Paronetto MP, Sette C (Jul 2011). "The RNA-binding protein Sam68 is a multifunctional player in human cancer" (PDF). Endocr Relat Cancer. 18 (4): R91–R102. doi:10.1530/ERC-11-0041. hdl:2108/88068. PMID 21565971.
  27. 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 (Dec 2005). "Ablation of the Sam68 RNA binding protein protects mice from age-related bone loss". PLOS Genet. 1 (6): e74. doi:10.1371/journal.pgen.0010074. PMC 1315279. PMID 16362077.
  28. Bianchi E, Barbagallo F, Valeri C, Geremia R, Salustri A, De Felici M, Sette C (Dec 2010). "Ablation of the Sam68 gene impairs female fertility and gonadotropin-dependent follicle development". Hum Mol Genet. 19 (24): 4886–94. doi:10.1093/hmg/ddq422. PMID 20881015.
  29. Lukong KE, Richard S (Jun 2008). "Motor coordination defects in mice deficient for the Sam68 RNA-binding protein". Behav Brain Res. 189 (2): 357–63. doi:10.1016/j.bbr.2008.01.010. PMID 18325609. S2CID 37887832.
  30. Richard S, Vogel G, Huot ME, Guo T, Muller WJ, Lukong KE (Jan 2008). "Sam68 haploinsufficiency delays onset of mammary tumorigenesis and metastasis". Oncogene. 27 (4): 548–56. doi:10.1038/sj.onc.1210652. PMID 17621265.

Further reading

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