KHDRBS1

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. 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. 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 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 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. == Gene knockout studies ==

Sam68-deficient mice were generated by targeted disruption of exons 4-5 of the sam68 gene, which encode the functional region of the KH domain. The genotypes of the offspring from heterozygote intercrosses exhibited a Mendelian segregation at E18.5. Despite the lack of visible deformity, many of the Sam68-/- pups died at birth of unknown causes. The Sam68-null mice exhibited motor coordination defects and fell from the rotating drum at lower speeds and prematurely compared to the wild-type controls. Sam68-/- mice are protected against age-induced osteoporosis. Kaplan-Meier curves showed that loss of one sam68 allele (PyMT; Sam68+/-) was associated with a significant delay in the onset of palpable tumors and a significant reduction in tumor multiplicity. These findings suggest that Sam68 is required for PyMT-induced mammary tumorigenesis. The knockdown of Sam68 expression in PyMT-derived mammary cells reduced the number of lung tumor foci in athymic mice, suggesting that Sam68 is also required for mammary tumor metastasis. ==References==