KHDRBS1

KHDRBS1
Available structures Gene ontology Molecular function DNA binding poly(A) binding poly(U) RNA binding SH3 domain binding protein-containing complex binding protein binding RNA binding nucleic acid binding protein domain specific binding identical protein binding Cellular component cytoplasm Grb2-Sos complex membrane nucleus cytosol nucleoplasm Biological process regulation of transcription, DNA-templated regulation of protein stability transcription, DNA-templated positive regulation of RNA export from nucleus cell surface receptor signaling pathway G2/M transition of mitotic cell cycle regulation of RNA export from nucleus cell cycle cell population proliferation negative regulation of transcription, DNA-templated positive regulation of translational initiation signal transduction mRNA processing positive regulation of signal transduction regulation of mRNA splicing, via spliceosome spermatogenesis protein complex oligomerization regulation of alternative mRNA splicing, via spliceosome G1/S transition of mitotic cell cycle Sources:Amigo / QuickGO
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 Mb Chr 4: 129.6 – 129.64 Mb PubMed search [3] [4]
Wikidata
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KH domain-containing, RNA-binding, signal transduction-associated protein 1 is a protein that in humans is encoded by the KHDRBS1 gene.^[5][6]

This gene encodes a member of the

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

Sam68 is also downstream of the

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

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

Further reading

• Najib S, Martín-Romero C, González-Yanes C, Sánchez-Margalet V (2005). "Role of Sam68 as an adaptor protein in signal transduction". Cell. Mol. Life Sci. 62 (1): 36–43.
  S2CID 21628826
  .
• Koch CA, Moran MF, Anderson D, et al. (1992). "Multiple SH2-mediated interactions in v-src-transformed cells". Mol. Cell. Biol. 12 (3): 1366–74.
  PMID 1545818
  .
• Weng Z, Thomas SM, Rickles RJ, et al. (1994). "Identification of Src, Fyn, and Lyn SH3-binding proteins: implications for a function of SH3 domains". Mol. Cell. Biol. 14 (7): 4509–21.
  PMID 7516469
  .
• Taylor SJ, Anafi M, Pawson T, Shalloway D (1995). "Functional interaction between c-Src and its mitotic target, Sam 68". J. Biol. Chem. 270 (17): 10120–4.
  PMID 7537265
  .
• Richard S, Yu D, Blumer KJ, et al. (1995). "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. 15 (1): 186–97.
  PMID 7799925
  .
• Nunès JA, Truneh A, Olive D, Cantrell DA (1996). "Signal transduction by CD28 costimulatory receptor on T cells. B7-1 and B7-2 regulation of tyrosine kinase adaptor molecules". J. Biol. Chem. 271 (3): 1591–8.
  PMID 8576157
  .
• Vadlamudi RK, Joung I, Strominger JL, Shin J (1996). "p62, a phosphotyrosine-independent ligand of the SH2 domain of p56lck, belongs to a new class of ubiquitin-binding proteins". J. Biol. Chem. 271 (34): 20235–7.
  PMID 8702753
  .
• Finan PM, Hall A, Kellie S (1996). "Sam68 from an immortalised B-cell line associates with a subset of SH3 domains". FEBS Lett. 389 (2): 141–4.
  PMID 8766817
  .
• Bunnell SC, Henry PA, Kolluri R, et al. (1996). "Identification of Itk/Tsk Src homology 3 domain ligands". J. Biol. Chem. 271 (41): 25646–56.
  PMID 8810341
  .
• Andreotti AH, Bunnell SC, Feng S, et al. (1997). "Regulatory intramolecular association in a tyrosine kinase of the Tec family". Nature. 385 (6611): 93–7.
  S2CID 25356409
  .
• Trüb T, Frantz JD, Miyazaki M, et al. (1997). "The role of a lymphoid-restricted, Grb2-like SH3-SH2-SH3 protein in T cell receptor signaling". J. Biol. Chem. 272 (2): 894–902.
  PMID 8995379
  .
• Lawe DC, Hahn C, Wong AJ (1997). "The Nck SH2/SH3 adaptor protein is present in the nucleus and associates with the nuclear protein SAM68". Oncogene. 14 (2): 223–31.
  PMID 9010224
  .
• Barlat I, Maurier F, Duchesne M, et al. (1997). "A role for Sam68 in cell cycle progression antagonized by a spliced variant within the KH domain". J. Biol. Chem. 272 (6): 3129–32.
  PMID 9013542
  .
• Fusaki N, Iwamatsu A, Iwashima M, Fujisawa J (1997). "Interaction between Sam68 and Src family tyrosine kinases, Fyn and Lck, in T cell receptor signaling". J. Biol. Chem. 272 (10): 6214–9.
  PMID 9045636
  .
• Guinamard R, Fougereau M, Seckinger P (1997). "The SH3 domain of Bruton's tyrosine kinase interacts with Vav, Sam68 and EWS". Scand. J. Immunol. 45 (6): 587–95.
  PMID 9201297
  .
• Resnick RJ, Taylor SJ, Lin Q, Shalloway D (1997). "Phosphorylation of the Src substrate Sam68 by Cdc2 during mitosis". Oncogene. 15 (11): 1247–53.
  PMID 9315091
  .
• Chen T, Damaj BB, Herrera C, et al. (1997). "Self-association of the single-KH-domain family members Sam68, GRP33, GLD-1, and Qk1: role of the KH domain". Mol. Cell. Biol. 17 (10): 5707–18.
  PMID 9315629
  .
• Tang J, Feng GS, Li W (1997). "Induced direct binding of the adapter protein Nck to the GTPase-activating protein-associated protein p62 by epidermal growth factor". Oncogene. 15 (15): 1823–32.
  PMID 9362449
  .
• Sung CK, Choi WS, Sanchez-Margalet V (1998). "Guanosine triphosphatase-activating protein-associated protein, but not src-associated protein p68 in mitosis, is a part of insulin signaling complexes". Endocrinology. 139 (5): 2392–8.
  PMID 9564850
  .

This article incorporates text from the United States National Library of Medicine, which is in the public domain.