| SAM68 (Src-associated in mitosis 68 kDa, KHDRBS1) is a KH-domain RNA-binding protein of the STAR family that couples signal transduction to RNA metabolism through modular domains that include an N-terminal region with multiple proline-rich and tyrosine motifs for SH2/SH3-containing partners, a central KH RNA-binding domain that recognizes UAAA-rich elements, and C-terminal low-complexity regions that support multimerization and assembly into ribonucleoprotein complexes. SAM68 associates with nascent transcripts and spliceosomal components at the chromatin interface, where it modulates alternative splicing of pre-mRNAs encoding regulators of proliferation, apoptosis, and migration, such as BCL-X, CCND1, and CD44, by recruiting or antagonizing core splicing factors and altering exon inclusion in response to upstream signaling cues. Post-translational modifications by Src family kinases, ERK, and other mitogenic pathways on tyrosine and serine/threonine residues modulate SAM68’s affinity for RNA and protein partners, shifting its localisation among the nucleus, cytoplasm, and stress granules, thereby linking receptor and oncogenic kinase activity to broad changes in transcript isoform output. In neural progenitor cells, SAM68 regulates gene programs that maintain self-renewal and glycolytic metabolism, where its control of mRNAs involved in glucose uptake, glycolytic enzyme expression, and cell-cycle regulators sustains proliferative, metabolically active states and influences the balance between progenitor expansion and differentiation during brain development. SAM68 also influences mRNA export, stability, and translation of selected transcripts, positioning it as an integrator of transcriptional and post-transcriptional control that can coordinate the timing and magnitude of signalling responses at multiple levels of gene expression. Elevated nuclear SAM68 expression and altered subcellular distribution correlate with aggressive behavior and poor prognosis in several human cancers, including non-small cell lung and colorectal cancer, where it shapes oncogenic signaling networks by controlling splicing and expression of genes that promote cell-cycle progression, survival, and invasive behavior. |
