KHDRBS3 explained

KH domain-containing, RNA-binding, signal transduction-associated protein 3 is a protein that in humans is encoded by the KHDRBS3 gene.^{[1] [2] [3]}

Interactions

KHDRBS3 has been shown to interact with SIAH1.^{[4] [5]}

KHDRBS3 interacts with splicing protein Sam68 and oncogene metadherin in prostate cancer cells.^[6]

Clinical significance

KHDRBS3 (T-STAR) expression has been shown to be increased in prostate cancer tissue compared to the surrounding benign tissue. Expression of KHDRBS3 correlates with mpMRI signal measured through Likert score a system similar to PI-RADS. While still under debate, mpMRI signal correlates with higher Gleason grade and tumour size, in addition to histopathological features associated with clinically aggressive prostate cancer.^{[7] [8]} Expression of KHDRBS3 was increased in the failing human myocardium of heart failure patients, here KHDRBS3 protein interacted with several important mRNAs coding for sarcomere components, such as actin gamma 1 (ACTG1), myosin light chain 2 (MYL2), ryanodine receptor 2 (RYR2), troponin I3 (TNNI3), troponin T2 (TNNT2), tropomyosin 1 (TPM1), tropomyosin 2 (TPM2), and titin (TTN).^[9]

In prostate cancer cell lines KHDRBS3 appears to be androgen regulated, with a reduction in mRNA expression occurring following addition of synthetic androgen R1881 to cells.

Function

KHDRBS3 regulates the alternative mRNA splicing of the sacromere protein titin (TTN), leading to intron retention. Overexpression of KHDRBS3 in induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) increased Ca²⁺ transient amplitude and resulted in an increase of F_max.

Further reading

• 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 . Proceedings of the National Academy of Sciences of the United States of America . 96 . 6 . 2710–5 . March 1999 . 10077576 . 15834 . 10.1073/pnas.96.6.2710 . 1999PNAS...96.2710D . free .
• Venables JP, Elliott DJ, Makarova OV, Makarov EM, Cooke HJ, Eperon IC . RBMY, a probable human spermatogenesis factor, and other hnRNP G proteins interact with Tra2beta and affect splicing . Human Molecular Genetics . 9 . 5 . 685–94 . March 2000 . 10749975 . 10.1093/hmg/9.5.685 . free .
• Stoss O, Olbrich M, Hartmann AM, Konig H, Memmott J, Andreadis A, Stamm S . The STAR/GSG family protein rSLM-2 regulates the selection of alternative splice sites . The Journal of Biological Chemistry . 276 . 12 . 8665–73 . March 2001 . 11118435 . 10.1074/jbc.M006851200 . free .
• Sugimoto Y, Morita R, Amano K, Shah PU, Pascual-Castroviejo I, Khan S, Delgado-Escueta AV, Yamakawa K . 28713407 . 6 . T-STAR gene: fine mapping in the candidate region for childhood absence epilepsy on 8q24 and mutational analysis in patients . Epilepsy Research . 46 . 2 . 139–44 . August 2001 . 11463515 . 10.1016/S0920-1211(01)00274-1 .
• Kool J, van Zaane W, van der Eb AJ, Terleth C . Down-regulation of T-STAR, a growth inhibitory protein, after SV40-mediated immortalization . Cell Growth & Differentiation . 12 . 11 . 535–41 . November 2001 . 11714634 .
• Reddy TR, Suhasini M, Xu W, Yeh LY, Yang JP, Wu J, Artzt K, Wong-Staal F . 6 . A role for KH domain proteins (Sam68-like mammalian proteins and quaking proteins) in the post-transcriptional regulation of HIV replication . The Journal of Biological Chemistry . 277 . 8 . 5778–84 . February 2002 . 11741900 . 10.1074/jbc.M106836200 . free .
• Côté J, Boisvert FM, Boulanger MC, Bedford MT, Richard S . Sam68 RNA binding protein is an in vivo substrate for protein arginine N-methyltransferase 1 . Molecular Biology of the Cell . 14 . 1 . 274–87 . January 2003 . 12529443 . 140244 . 10.1091/mbc.E02-08-0484 .
• Venables JP, Dalgliesh C, Paronetto MP, Skitt L, Thornton JK, Saunders PT, Sette C, Jones KT, Elliott DJ . 6 . SIAH1 targets the alternative splicing factor T-STAR for degradation by the proteasome . Human Molecular Genetics . 13 . 14 . 1525–34 . July 2004 . 15163637 . 10.1093/hmg/ddh165 .
• Cohen CD, Doran PP, Blattner SM, Merkle M, Wang GQ, Schmid H, Mathieson PW, Saleem MA, Henger A, Rastaldi MP, Kretzler M . 6 . Sam68-like mammalian protein 2, identified by digital differential display as expressed by podocytes, is induced in proteinuria and involved in splice site selection of vascular endothelial growth factor . Journal of the American Society of Nephrology . 16 . 7 . 1958–65 . July 2005 . 15901763 . 10.1681/ASN.2005020204 . free .
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . 4427026 . 6 . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–8 . October 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R .
• Zhang L, Guo L, Peng Y, Chen B . Expression of T-STAR gene is associated with regulation of telomerase activity in human colon cancer cell line HCT-116 . World Journal of Gastroenterology . 12 . 25 . 4056–60 . July 2006 . 16810759 . 4087721 . 10.3748/wjg.v12.i25.4056 . free .
• Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M . 7827573 . Global, in vivo, and site-specific phosphorylation dynamics in signaling networks . Cell . 127 . 3 . 635–48 . November 2006 . 17081983 . 10.1016/j.cell.2006.09.026 . free .

Notes and References

1. Venables JP, Vernet C, Chew SL, Elliott DJ, Cowmeadow RB, Wu J, Cooke HJ, Artzt K, Eperon IC . 6 . T-STAR/ETOILE: a novel relative of SAM68 that interacts with an RNA-binding protein implicated in spermatogenesis . Human Molecular Genetics . 8 . 6 . 959–69 . June 1999 . 10332027 . 10.1093/hmg/8.6.959 . free .
2. Lee J, Burr JG . Salpalpha and Salpbeta, growth-arresting homologs of Sam68 . Gene . 240 . 1 . 133–47 . November 1999 . 10564820 . 10.1016/S0378-1119(99)00421-7 .
3. Web site: Entrez Gene: KHDRBS3 KH domain containing, RNA binding, signal transduction associated 3.
4. Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . 4427026 . 6 . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–8 . October 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R . Huda Zoghbi .
5. Venables JP, Dalgliesh C, Paronetto MP, Skitt L, Thornton JK, Saunders PT, Sette C, Jones KT, Elliott DJ . 6 . SIAH1 targets the alternative splicing factor T-STAR for degradation by the proteasome . Human Molecular Genetics . 13 . 14 . 1525–34 . July 2004 . 15163637 . 10.1093/hmg/ddh165 .
6. Luxton HJ, Simpson BS, Mills IG, Brindle NR, Ahmed Z, Stavrinides V, Heavey S, Stamm S, Whitaker HC . 6 . 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 . August 2019 . 1233 . 31450747 . 6770463 . 10.3390/cancers11091233 . free .
7. Norris JM, Carmona Echeverria LM, Bott SR, Brown LC, Burns-Cox N, Dudderidge T, El-Shater Bosaily A, Frangou E, Freeman A, Ghei M, Henderson A, Hindley RG, Kaplan RS, Kirkham A, Oldroyd R, Parker C, Persad R, Punwani S, Rosario DJ, Shergill IS, Stavrinides V, Winkler M, Whitaker HC, Ahmed HU, Emberton M . 6 . What Type of Prostate Cancer Is Systematically Overlooked by Multiparametric Magnetic Resonance Imaging? An Analysis from the PROMIS Cohort . European Urology . May 2020 . 78 . 2 . 163–170 . 32370911 . 10.1016/j.eururo.2020.04.029 . 7397509 . free .
8. Norris JM, Carmona Echeverria LM, Simpson BS, Allen C, Ball R, Freeman A, Kelly D, Kirkham A, Kasivisvanathan V, Whitaker HC, Emberton M . 6 . Prostate cancer visibility on multiparametric magnetic resonance imaging: high Gleason grade and increased tumour volume are not the only important histopathological features . BJU International . April 2020 . 126 . 2 . 237–239 . 32319152 . 10.1111/bju.15085 . free .
9. Boeckel. Jes-Niels. Möbius-Winkler. Maximilian. Müller. Marion. Rebs. Sabine. Eger. Nicole. Schoppe. Laura. Tappu. Rewati. Kokot. Karoline E.. Kneuer. Jasmin M.. Gaul. Susanne. Bordalo. Diana M.. 2021-07-15. SLM2 Is A Novel Cardiac Splicing Factor Involved in Heart Failure due to Dilated Cardiomyopathy. Genomics, Proteomics & Bioinformatics. 20 . 1 . 129–146 . en. 10.1016/j.gpb.2021.01.006. 34273561 . 9510876 . 1672-0229. free.