KH RNA binding domain-containing signal transduction-associated protein 1 (KHDRBS1) (KHDRBS1)

KH RNA binding domain-containing signal transduction-associated protein 1 (KHDRBS1), commonly known as Sam68, is a multifunctional RNA-binding protein that serves as a critical link between cellular signaling and RNA processing [1, 2]. It belongs to the Signal Transduction and Activation of RNA (STAR) family and contains a KH domain that facilitates binding to AU-rich sequences in target mRNAs [1, 3]. KHDRBS1 is regulated by post-translational modifications, such as tyrosine phosphorylation by Src-family kinases, which influence its ability to regulate alternative splicing, mRNA stability, and translation [3, 5]. In the context of disease, KHDRBS1 is frequently upregulated in various cancers, where it promotes the expression of oncogenic splice variants of genes like CD44 and BCL-X, thereby driving tumor cell proliferation and survival [3, 4]. It also plays a pivotal role in the pathogenesis of Spinal Muscular Atrophy (SMA) by modulating the splicing of the SMN2 gene, making it a target for therapeutic intervention [4, 6]. Although no drugs targeting KHDRBS1 are currently FDA-approved, research is actively exploring the use of antisense oligonucleotides (ASOs) and small molecules to inhibit its activity or correct the splicing defects it induces [5, 6]. Its broad involvement in essential cellular processes presents a challenge for drug development, as systemic inhibition may lead to widespread off-target effects on RNA metabolism [1, 5].

Other names

Sam68Src-associated in mitosis 68 kDa proteinp68GAP-associated tyrosine phosphoprotein p62SALP

Modulation of alternative splicing and inhibition of RNA-protein interactions