Disease relevance of KHDRBS1

• Tyrosine phosphorylation of sam68 by breast tumor kinase regulates intranuclear localization and cell cycle progression [1].
• Sam68, RNA helicase A and Tap cooperate in the post-transcriptional regulation of human immunodeficiency virus and type D retroviral mRNA [2].
• Salpalpha is tyrosine-phosphorylated when expressed in Rous sarcoma virus-infected chicken embryo fibroblasts (RSV-CEF); unlike Sam68, however, Salpalpha does not co-precipitate with v-Src [3].
• Inhibition of HIV replication by dominant negative mutants of Sam68, a functional homolog of HIV-1 Rev [4].
• Thus, Sam68 may play an important role in the post-transcriptional regulation of all complex retroviruses [5].

High impact information on KHDRBS1

• We demonstrated that tyrosine phosphorylation of p68 at Y593 mediated PDGF-stimulated epithelial-mesenchymal transition (EMT) [6].
• In the present study, we characterized the tyrosine phosphorylation of p68 under platelet-derived growth factor (PDGF) stimulation [6].
• We showed that PDGF treatment led to phosphorylation of p68 at Y593 in the cell nucleus [6].
• p62 is a tyrosine phosphoprotein that associates with p21ras GTPase-activating protein (GAP) [7].
• The double-stranded (ds) RNA-dependent protein kinase is a 100,000-110,000 Mr complex of two interferon-induced subunits each having ATP binding sites: a 48,000 Mr protein (p48) which appears to be responsible for the phosphorylation of a 68,000 Mr protein (p68) in the presence of dsRNA [8].

Chemical compound and disease context of KHDRBS1

• In cultured cells infected with vaccinia virus and transfected with a plasmid containing the p68 gene, there is synthesis of p68 when lacl repressor is inhibited with isopropyl-beta-D-thiogalactoside [9].
• Levels of p62 c-myc varied in colorectal cancer and low levels (less than 20 fluorescein units) correlated with improved survival (log rank chi 2 = 4.69, df = 1, P = 0.03), and this was a better prognostic index than DNA ploidy (log rank analysis chi 2 = 2.38, df = 1, P less than 0.1) [10].

Biological context of KHDRBS1

• CD3 cross-linking induced tyrosine phosphorylation of Sam68 in uninfected T cells [11].
• Purification and microsequencing of this protein revealed that it was the RNA-binding protein, Sam68 (Src associated in mitosis, 68 kDa) [11].
• These data suggest that Sam68 participates in the signal transduction pathway downstream of TCR-coupled Src family kinases Fyn and Lck in lymphocytes, that is not only in the mitotic pathway downstream of c-Src in fibroblasts [11].
• Over-expression of Sam68 activates both RRE- and CTE-regulated reporter gene expression in human cells and in quail cells in the presence of human Tap [2].
• We further showed that Sam68, but not a non-functional mutant Sam68p21, inhibited transcriptional activation of CT element by hnRNP K [12].

Anatomical context of KHDRBS1

• Interaction between Sam68 and Src family tyrosine kinases, Fyn and Lck, in T cell receptor signaling [11].
• Tyrosine 440 was identified as a principal modulator of Sam68 localization and this site was phosphorylated in response to EGF treatment in human breast tumor cell lines [1].
• It has been further established that Sam68 is a substrate of src kinases in mitosis and that it is not associated with p120GAP in transformed fibroblasts [13].
• We propose that recruitment of Sam68, via CD4/p56lck, to the inner face of the plasma membrane may permit, via its docking properties, the correct association of key signaling molecules including PLC gamma 1 and p120GAP [13].
• Sam68 from an immortalised B-cell line associates with a subset of SH3 domains [14].

Associations of KHDRBS1 with chemical compounds

• Synthetic peptides corresponding to the proline motifs of Sam68 inhibited with different efficiencies the binding of SH3 domains to Sam68 suggesting that the proline motifs of Sam68 function as specific SH3 domain binding sites [15].
• Guanosine triphosphatase-activating protein-associated protein, but not src-associated protein p68 in mitosis, is a part of insulin signaling complexes [16].
• In vivo studies of protein-protein interaction were assessed by co-immunoprecipitation experiments with specific antibodies against Sam68, GAP, Grb2, SOS, and phosphotyrosine; and by affinity precipitation with the fusion proteins (SH3-Grb2) [17].
• The presence of p72/p68 potentiated the estrogen-induced expression of the endogenous pS2 gene in MCF7 cells [18].
• We demonstrate that p68 enhanced the activity of AF-1 but not AF-2 and the estrogen-induced as well as the anti-estrogen-induced transcriptional activity of the full-length ERalpha in a cell-type-specific manner [19].

Physical interactions of KHDRBS1

• Here we describe the identification of heterogeneous nuclear ribonucleoprotein K (hnRNP K) as a protein that specifically interacts with Sam68 in vitro and in vivo [12].
• RHA binds to Sam68 and to Tap both in vivo and in vitro [2].
• We have identified a region within the p53 TAD that specifically interacts with the pleckstrin homology (PH) domain of the p62 and Tfb1 subunits of human and yeast TFIIH [20].
• By using the differential display and cDNA-representational difference analysis techniques, followed by reverse transcription polymerase chain reaction of RNAs co-immunoprecipitated with Sam68 from a HeLa cell lysate, we identified 10 mRNA species that bind in vivo to Sam68 in an RNA-binding domain-dependent manner [21].

Enzymatic interactions of KHDRBS1

• We also show that recombinant forms of both p56(lck) and ZAP-70 phosphorylate Sam68 in vitro [22].

Regulatory relationships of KHDRBS1

• Sam68 enhances the cytoplasmic utilization of intron-containing RNA and is functionally regulated by the nuclear kinase Sik/BRK [23].
• A dual participation of ZAP-70 and scr protein tyrosine kinases is required for TCR-induced tyrosine phosphorylation of Sam68 in Jurkat T cells [22].
• SUMO modification of Sam68 enhances its ability to repress cyclin D1 expression and inhibits its ability to induce apoptosis [24].

Other interactions of KHDRBS1

• The regulation of p62 is a unique CD28 response that is not shared with the TCR [25].
• Three of them were characterized as Vav, Sam68 and EWS [26].
• Sam68 was initially described as associated with p120GAP [13].
• Sam68 is a target of the c-Src tyrosine kinase [12].
• The ability of proline-rich peptides homologous to the Sam68 primary sequence to inhibit the binding of Sam68 to SH3 domains was investigated [14].

Analytical, diagnostic and therapeutic context of KHDRBS1

• By indirect immunofluorescence we observed that BRK and EGF treatment not only phosphorylates Sam68 but also induces its relocalization [1].
• Immunoblotting identified this protein as human Sam68 [14].
• Molecular cloning and nucleic acid binding properties of the GAP-associated tyrosine phosphoprotein p62 [7].
• Evidence for a role for SAM68 in the responses of human neutrophils to ligation of CD32 and to monosodium urate crystals [27].
• We have used site-directed mutagenesis of the two GAP SH2 domains (SH2-N and SH2-C) to identify residues involved in receptor and p62 binding [28].

References