KHDRBS1

Description

The KHDRBS1 (KH RNA binding domain containing, signal transduction associated 1) is a protein-coding gene located on chromosome 1.

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. 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). 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. 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.

KHDRBS1 is recruited and tyrosine phosphorylated by various receptor systems, including the T-cell, leptin, and insulin receptors. Upon phosphorylation, it functions as an adapter protein in signal transduction cascades by interacting with proteins containing SH2 and SH3 domains. It plays a role in G2-M progression during the cell cycle. KHDRBS1 represses CBP-dependent transcriptional activation by competing with other nuclear factors for binding to CBP. It also acts as a potential regulator of mRNA stability and/or translation rates, mediating mRNA nuclear export. KHDRBS1 positively regulates the association of constitutive transport element (CTE)-containing mRNA with large polyribosomes and translation initiation. However, some studies suggest it is not involved in the nucleocytoplasmic export of unspliced (CTE)-containing RNA species. KHDRBS1 is an RNA-binding protein that regulates alternative splicing, influencing mRNA splice site selection and exon inclusion. It binds to RNA containing the 5'-[AU]UAA-3' bipartite motif, spaced by more than 15 nucleotides, and binds poly(A). KHDRBS1 can regulate CD44 alternative splicing in a Ras pathway-dependent manner. In cooperation with HNRNPA1, it modulates alternative splicing of BCL2L1 by promoting splicing toward the Bcl-X(S) isoform and SMN1. KHDRBS1 can also regulate alternative splicing of NRXN1 and NRXN3 in the laminin G-like domain 6, which contains the evolutionary conserved neurexin alternative spliced segment 4 (AS4) involved in neurexin selective targeting to postsynaptic partners. In a neuronal activity-dependent manner, it cooperates synergistically with KHDRBS2/SLIM-1 in regulating NRXN1 exon skipping at AS4. This cooperation with KHDRBS2/SLIM-1 is antagonistic for regulating NXRN3 alternative splicing at AS4.

KHDRBS1 is also known as Sam68, p62, p68.

Associated Diseases

WES Whole Exome Sequencing