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Gene Review

Khdrbs1  -  KH domain containing, RNA binding, signal...

Mus musculus

Synonyms: GAP-associated tyrosine phosphoprotein p62, KH domain-containing, RNA-binding, signal transduction-associated protein 1, Sam68, Src-associated in mitosis 68 kDa protein, p21 Ras GTPase-activating protein-associated p62, ...
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Disease relevance of Khdrbs1


High impact information on Khdrbs1


Biological context of Khdrbs1

  • Herein we have investigated the expression and function during mammalian male meiosis of Sam68, an RNA-binding protein implicated in several aspects of RNA metabolism [8].
  • Both kinases associate with Sam68 in pachytene spermatocytes and phosphorylate the regulatory regions upstream and downstream of the Sam68 RNA-binding motif [8].
  • Analysis of correlations between gene expression and behavioural data revealed connection between the level of mRNA for K homology domain containing, RNA binding, signal transduction associated 1 (Khdrbs1) and ATPase Na+/K+ alpha2 subunit (Atp1a2) with morphine self-administration and analgesic effects, respectively [9].
  • Consistent with these results is evidence that cells undergoing mitosis show a dramatic reduction in the level of Sam68 protein [10].
  • Whereas simple haploinsufficiency of Sam68 produced by insertion mutagenesis in a single chromosomal allele did not detectably affect cell growth, reduction of Sam68 protein to <25% of the wild type level was associated with anchorage-independent growth, defective contact inhibition, and the ability to form metastatic tumors in nude mice [10].

Anatomical context of Khdrbs1

  • We also demonstrate that Sam68 shuttles between the nucleus and the cytoplasm in secondary spermatocytes, suggesting that it may promote translation of specific RNA targets during the meiotic divisions [8].
  • During the meiotic divisions, Sam68 translocates to the cytoplasm where it is found associated with the polysomes [8].
  • Sam68 expression and localization within the cells is stage specific: it is expressed in the nucleus of spermatogonia, it disappears at the onset of meiosis (leptotene/zygotene stages), and it accumulates again in the nucleus of pachytene spermatocytes and round spermatids [8].
  • Here we report that RHKO-induced Sam68 deficiency results in neoplastic transformation of murine NIH3T3 fibroblasts [10].
  • Fyn membrane localization is necessary to induce the constitutive tyrosine phosphorylation of Sam68 in the nucleus of T lymphocytes [11].

Associations of Khdrbs1 with chemical compounds

  • Second, the phosphotyrosine content of p190 in cells overexpressing defective pp60c-src is reduced in comparison with wild-type (wt) c-src overexpressors, while that of p62 is significantly less affected [12].
  • Cultures of mouse embryo fibroblasts generated from Sam68+/+ and Sam68-/- littermates were induced to differentiate into adipocytes with culture medium containing pioglitazone and the Sam68-/- mouse embryo fibroblasts shown to have impaired adipocyte differentiation [1].
  • Purification of p68 was achieved by passage of a 100 000 X g supernatant fraction over DEAE-cellulose, fractionation with ammonium sulfate, and chromatography on hydroxylapatite [3].

Enzymatic interactions of Khdrbs1

  • Sam68 is the major tyrosine-phosphorylated and Src-associated protein in mitotic cells [13].

Other interactions of Khdrbs1

  • We find that Sam68 phosphorylation, including in the nuclear fraction in which the molecule is predominantly expressed, is lost with a delocalized Fyn mutant deleted of its N-terminal membrane-anchoring domain [11].
  • RACK1 regulates Src-mediated Sam68 and p190RhoGAP signaling [14].
  • Sam68 stimulates G1/S transition and this effect is dependent on the integrity of its KH domain (hnRNPK Homology) which confers nucleic acid binding properties [13].

Analytical, diagnostic and therapeutic context of Khdrbs1

  • Radicicol reversibly inhibits the mitosis-specific tyrosine phosphorylation of Sam68 in vivo, as determined by antiphosphotyrosine immunoblotting [15].
  • However, the interaction of Ras-GAP with Sam68 has been brought into question, based on the lack of co-immunoprecipitation between Sam68 and Ras-GAP in interphase cells [13].
  • Immunofluorescence analysis showed that while either singly expressed p180 or p68 was localized in the cytoplasm, cotransfection of both subunits resulted in colocalization in the nucleus [16].
  • Furthermore, as determined by confocal microscopy, deletion of the p62 UBA domain impaired the association of p62 with TRAF6 in the proteasomal compartment [2].
  • Cell lines that reached the advanced stage of feeder-independent agar growth showed increased detection by antiphosphotyrosine Western blot of the GAP-associated p62 phosphoprotein as well as of a 55 kDa phosphoprotein while detection of the P160 v-abl phosphoprotein remained constant throughout all stages of progression [17].


  1. Ablation of the Sam68 RNA binding protein protects mice from age-related bone loss. Richard, S., Torabi, N., Franco, G.V., Tremblay, G.A., Chen, T., Vogel, G., Morel, M., Cléroux, P., Forget-Richard, A., Komarova, S., Tremblay, M.L., Li, W., Li, A., Gao, Y.J., Henderson, J.E. PLoS Genet. (2005) [Pubmed]
  2. p62 ubiquitin binding-associated domain mediated the receptor activator of nuclear factor-kappaB ligand-induced osteoclast formation: a new insight into the pathogenesis of Paget's disease of bone. Yip, K.H., Feng, H., Pavlos, N.J., Zheng, M.H., Xu, J. Am. J. Pathol. (2006) [Pubmed]
  3. A 68 000 dalton protein genetically associated with corticotropin-sensitive adenylate cyclase activity. Purification and preliminary characterization using a specific antiserum. Schimmer, B.P., Robinson, R., Tsao, J., Watt, V.M. Can. J. Biochem. Cell Biol. (1984) [Pubmed]
  4. Role of the second-largest subunit of DNA polymerase alpha in the interaction between the catalytic subunit and hyperphosphorylated retinoblastoma protein in late S phase. Takemura, M., Yoshida, S., Akiyama, T., Kitagawa, M., Yamada, Y. Biochim. Biophys. Acta (2006) [Pubmed]
  5. A target for Src in mitosis. Fumagalli, S., Totty, N.F., Hsuan, J.J., Courtneidge, S.A. Nature (1994) [Pubmed]
  6. The signaling adapter p62 is an important mediator of T helper 2 cell function and allergic airway inflammation. Martin, P., Diaz-Meco, M.T., Moscat, J. EMBO J. (2006) [Pubmed]
  7. Identification of Src, Fyn, and Lyn SH3-binding proteins: implications for a function of SH3 domains. Weng, Z., Thomas, S.M., Rickles, R.J., Taylor, J.A., Brauer, A.W., Seidel-Dugan, C., Michael, W.M., Dreyfuss, G., Brugge, J.S. Mol. Cell. Biol. (1994) [Pubmed]
  8. The nuclear RNA-binding protein Sam68 translocates to the cytoplasm and associates with the polysomes in mouse spermatocytes. Paronetto, M.P., Zalfa, F., Botti, F., Geremia, R., Bagni, C., Sette, C. Mol. Biol. Cell (2006) [Pubmed]
  9. Gene expression profiling in the striatum of inbred mouse strains with distinct opioid-related phenotypes. Korostynski, M., Kaminska-Chowaniec, D., Piechota, M., Przewlocki, R. BMC Genomics (2006) [Pubmed]
  10. Neoplastic transformation and tumorigenesis associated with sam68 protein deficiency in cultured murine fibroblasts. Liu, K., Li, L., Nisson, P.E., Gruber, C., Jessee, J., Cohen, S.N. J. Biol. Chem. (2000) [Pubmed]
  11. Fyn membrane localization is necessary to induce the constitutive tyrosine phosphorylation of Sam68 in the nucleus of T lymphocytes. Lang, V., Semichon, M., Michel, F., Brossard, C., Gary-Gouy, H., Bismuth, G. J. Immunol. (1999) [Pubmed]
  12. Increased levels of p21ras-GTP and enhanced DNA synthesis accompany elevated tyrosyl phosphorylation of GAP-associated proteins, p190 and p62, in c-src overexpressors. Chang, J.H., Wilson, L.K., Moyers, J.S., Zhang, K., Parsons, S.J. Oncogene (1993) [Pubmed]
  13. Sam68 is a Ras-GAP-associated protein in mitosis. Guitard, E., Barlat, I., Maurier, F., Schweighoffer, F., Tocque, B. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  14. RACK1 regulates Src-mediated Sam68 and p190RhoGAP signaling. Miller, L.D., Lee, K.C., Mochly-Rosen, D., Cartwright, C.A. Oncogene (2004) [Pubmed]
  15. Radicicol inhibits tyrosine phosphorylation of the mitotic Src substrate Sam68 and retards subsequent exit from mitosis of Src-transformed cells. Pillay, I., Nakano, H., Sharma, S.V. Cell Growth Differ. (1996) [Pubmed]
  16. The second-largest subunit of the mouse DNA polymerase alpha-primase complex facilitates both production and nuclear translocation of the catalytic subunit of DNA polymerase alpha. Mizuno, T., Ito, N., Yokoi, M., Kobayashi, A., Tamai, K., Miyazawa, H., Hanaoka, F. Mol. Cell. Biol. (1998) [Pubmed]
  17. Increased detection of specific tyrosine phosphoproteins correlates with tumor progression of Abelson virus-infected lymphocytes. Clark, S.S., Liang, Y. Leukemia (1995) [Pubmed]
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