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). 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. 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. Adipogenesis Sam68 influences alternative splicing of the mTOR kinase contributing to the lean phenotype observed in the Sam68 deficient mice. 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. 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. CD44 is a cell surface protein whose expression has been linked to cancer, with its expression predicting prognosis in a number of tumour types. In prostate cancer, Sam68 also interacts with splicing complex proteins KHDRBS3 (T-STAR) and Metadherin (MTDH) which also alter CD44 splicing. Subsequently, the knockdown of Sam68 has been shown to delay LNCaP prostate cancer cells proliferation. 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 RNA binding