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KHDRBS1
KH domain-containing, RNA-binding, signal transduction-associated protein 1 is a protein that in humans is encoded by the ''KHDRBS1'' gene.
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.
== 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. 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). 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. 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. 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. Sam68 was demonstrated to be involved in the alternative splicing of mRNAs implicated in normal neurogenesis using splicing-sensitive microarrays. Sam68 was also shown to participate in the epithelial-to-mesenchymal transition by regulating the alternative splicing of SF2/ASF.〔 Sam68 was shown to regulate the activity-dependent alternative splicing of the neurexin-1 in the central nervous system with implications for neurodevelopment disorders. Sam68 influences alternative splicing of the mTOR kinase contributing to the lean phenotype observed in the Sam68 deficient mice.
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. For example, the Sam68-dependent CD44 alternative splicing of exon v5 is regulated by ERK phosphorylation of Sam68〔 and Bcl-x alternative splicing is regulated by the p59fyn-dependent phosphorylation of Sam68.〔 Sam68 is also downstream of the epidermal growth factor receptor (EGFR), hepatocyte growth factor (HGF)/Met receptor (c-Met), leptin and tumor necrosis factor (TNF) receptors. 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 and regulates cell migration.〔
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