RBM10

Last updated
RBM10
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases RBM10 , DXS8237E, GPATC9, GPATCH9, S1-1, TARPS, ZRANB5, RNA binding motif protein 10
External IDs OMIM: 300080 MGI: 2384310 HomoloGene: 31330 GeneCards: RBM10
Orthologs
SpeciesHumanMouse
Entrez

8241

236732

Ensembl

ENSG00000182872

ENSMUSG00000031060

UniProt

P98175
Q7Z3D7

Q99KG3

RefSeq (mRNA)

NM_001204466
NM_001204467
NM_001204468
NM_005676
NM_152856

Contents

RefSeq (protein)
Location (UCSC) Chr X: 47.15 – 47.19 Mb Chr X: 20.48 – 20.52 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

RNA-binding motif 10 is a protein that is encoded by the RBM10 gene. [5] [6] [7] [8] This gene maps on the X chromosome at Xp11.23 in humans. RBM10 is a regulator of alternative splicing. [9] [10] [11] Alternative splicing is a process associated with gene expression to produce multiple protein isoforms from a single gene, thereby creating functional diversity and cellular complexity. [12] RBM10 influences the expression of many genes, [9] [10] [13] [14] [15] participating in various cellular processes and pathways such as cell proliferation and apoptosis. [10] [16] Its mutations are associated with various human diseases [17] [18] [19] [20] [21] [22] such as TARP syndrome, [22] [17] an X-linked congenital disorder in males resulting in pre‐ or postnatal lethality, and various cancers in adults. [18] [19]

Gene and protein

The RBM10 gene spans ~41.6 kb and contains 24 exons. This gene is subjected to X-inactivation, [6] [7] in which one of the two RBM10 genes in female cells is transcriptionally silenced by heterochromatin formation.

RBM proteins constitute a large family of RNA-binding proteins (RBPs). There are 52 RBM proteins (HGNC: HUGO Gene Nomenclature Committee), each containing one to several RNA-binding domains called RNA recognition motifs (RRMs). RBM10 contains two RRMs (RRM1 and RRM2) and other domains such as two zinc fingers (ZnFs), an octamer repeat (OCRE), three nuclear localization signals (NLSs), and a glycine-rich domain (G-patch). The amino acid (aa) sequence of RBM10 is conserved among mammals. Human RBM10 isoform 1 shares 96% and 97% sequence homology with those of mice and rats, respectively, indicating that the molecular functions of RBM10 are essentially the same in humans and rodents.

RBM10 has multiple isoforms, generated via alternative splicing events of the RBM10 primary transcript. The main isoforms, 1–4, may contain an exon 4 sequence (77 residues) and/or a Val residue corresponding to the last codon of exon 10. Isoform 1 (930 residues) contains both the exon 4 sequence and V354, whereas isoform 4 (929 residues) does not contain this valine residue. Similarly, the exon 4–minus isoform 3 (853 residues) contains V277, whereas isoform 2 (852 residues) does not. Isoform 5 (995 residues) has a longer 65-aa N-terminus, compared with that of isoform 1. In addition, automated computational analysis using the Gnomon gene prediction tool (NCBI gene) has shown that there may be more than 10 different RBM isoforms.

Function

RBM10 is ubiquitously expressed in almost every type of cell, both growing as well as quiescent (UniProtKB-P98175 [human] and Q99KG3 [mouse]; The Human Protein Atlas). In general, it is more strongly expressed in actively transcribing cells. [23]

In the alternative splicing regulation, RBM10 promotes the exclusion of an exon, called a cassette or alternative exon, from target pre-mRNAs, and less frequently, other alternative splicing events such as alternative 5ʹ-splice site selection. [9] [10] [11] [24] In the exon skipping process, RBM10 binds close to the 3ʹ- and 5ʹ-splice sites of cassette exons and interferes with the recognition and/or the pairing of the splice sites, thereby enhancing the pairing of the splice sites distal to the cassette exons, which ultimately leads to the exclusion of the exons together with the flanking upstream and downstream introns. [9] [10] [24]

The diversity of target RNAs bound by RBM10 in cells suggests that it is involved in various metabolic processes such as oxidative phosphorylation; pathways linked to cell proliferation, apoptosis, cell adhesion, and actin/cytoskeleton reorganization; and various diseases such as cancers and neurodegenerative diseases. [10] [16] [25] These data, together with the ubiquitous expression of RBM10, indicate that it is a fundamental cellular component participating in various cellular processes. In addition to alternative splicing regulation, RBM10 participates in other reactions. Some examples are polyadenylation of cardiac pre-mRNAs of anti-hypertrophy regulators, wherein it acts as a co-regulator of STAR-poly(A) polymerase, [26] stabilization of angiotensin II receptor mRNA by binding to its 3ʹ-UTR, [27] let-7g miRNA biogenesis through interaction with its precursor, [28] p53 stabilization by binding to its negative regulator, MDM2, [29] cell cycle arrest, [30] [31] and anti-viral reactions. [32]

RBM10 localizes to the nucleoplasm, where transcription and splicing occur, as well as in membrane-less nuclear compartments called S1-1 nuclear bodies (S1-1 NBs). [23] The numbers (ca. 10–40 per nucleus) and sizes (ca. 0.5 µm) of S1-1 NBs vary with the cell type and cellular conditions. When RNA polymerase II transcription decreases, RBM10 in the nucleoplasm is sequestered in S1-1 NBs, which become larger and spherical; when transcription is restored, RBM10 and the S1-1 NBs return to their initial states. [23] S1-1 NBs often overlap with nuclear speckles (also known as splicing speckles or interchromatin granule clusters), [23] [33] seemingly indicating a close functional relationship between these nuclear domains, i.e., alternative splicing regulation and splicing reaction.

Regulation

In females, most genes on one of the two X chromosomes are transcriptionally silenced by heterochromatin formation, and RBM10 is subjected to this X-inactivation. [6] [7] [34] In addition, there are mechanisms to control elevated cellular levels of RBM10. RBM10 auto-regulates its overexpressed pre-mRNA by alternative splicing to exclude exon 6 or 12, which generates a premature stop codon in the transcripts, leading to their degradation through nonsense-mediated mRNA decay (NMD). [14] When RNA polymerase II transcription decreases, RBM10 is sequestered in S1-1 NBs until transcription is restored. [23] In addition, RBM10 undergoes post-translational modifications: phosphorylation at many sites in response to various stimuli and changes in cellular conditions (UniProtKB-P98175; PhosphoSitePlus RBM10), as well as ubiquitylation, [35] [36] acetylation, [37] and methylation. [38] However, the molecular and biological significance of these various post-translational modifications of RBM10 is not well understood.

Clinical significance

Mutations in RBM10 are associated with various human diseases. The phenotypes caused by RBM10 mutations differ by the stages of development and affected tissues. Typical examples are TARP syndrome, an X-linked pleiotropic developmental malformation in neonates, [17] [22] and various cancers such as lung adenocarcinoma (LUAD) [18] and bladder carcinoma (BLCA) in adults. [19] These diseases are more common in males than in females. [39] [40] [41] One reason for this is the difference in the copy number of the RBM10 gene in a cell (one in male cells and two in female cells). Mutations in RBM10 occur throughout the molecule, and many of them are null mutations. TARP syndrome is generally pre- or postnatally lethal. [17] [42] [43] However, patients aged 11, 14, and 28 years have been reported to escape these null mutations. [44] [9] [45] RBM10 mutations have also been identified in other cancers [46] such as renal carcinomas, [47] [48] [49] pancreatic cancers, [50] [51] colorectal cancers, [52] [53] thyroid cancers, [54] [55] [56] breast cancers, [57] bile duct cancers, [58] [59] prostate cancer, [57] and brain tumor meningiomas and astroblastomas. [60] [61]

NUMB is the most studied downstream effector of RBM10. RBM10 promotes the skipping of exon 9 of the NUMB transcript, producing a NUMB isoform that causes ubiquitination followed by proteasomal degradation of the Notch receptor, and thereby inhibits the Notch signaling cell-proliferation pathway. [10] [62] [20] In various cancers, RBM10 mutations that inactivate or reduce its alternative splicing regulatory activity enhance the production of the exon 9–including NUMB isoform, which promotes cancer cell proliferation through the Notch pathway. [10] [63] [64]

RBM10 suppresses cell proliferation [10] [27] [63] [64] [65] [66] [29] and promotes apoptosis. [27] [64] [65] [29] [67] [68] Hence, it is generally regarded as a tumor suppressor. However, in certain cases, it may exert an opposite oncogenic function by acting as a tumor promoter or growth enhancer, [16] [69] [70] presumably due to the cellular contexts composed of different constituents and active pathways. A typical example of this is patients with pancreatic ductal adenocarcinoma (PDAC) having RBM10 mutations, who exhibit a survival rate remarkably higher than the general 5-year PDAC survival rate of less than 7–8%. [50] [71] [72]

Paralogs and splicing network

RBM5 and RBM6 are paralogs of RBM10. They were generated by gene duplications during genome evolution. They generally function as tumor suppressors, [10] [73] [74] [75] [76] [77] [78] [79] and their mutations are often identified in lung cancers. [21] RBM5, RBM6, and RBM10 regulate alternative splicing [10] [80] [81] and generally act on different RNAs; however, in certain cases, they act on the same subset of RNAs, likely producing synergistic or antagonistic effects. [10] There is a cross-regulation between RBM5 and RBM10; RBM10 lowers RBM5 transcript levels by alternative splicing–coupled NMD. [14] Furthermore, RBM10 perturbation (knockdown or overexpression) brings about splicing alterations in multiple splicing regulators, including RBM5, and also significantly influences the expression of other splicing regulators, including RBM10 itself. [9] [14] In addition, RBM10 primary transcripts are subjected to alternative splicing at several exons by unidentified splicing regulators, leading to the generation of multiple RBM10 isoforms. These data suggest the existence of an alternative splicing network formed by RBM5, RBM6, and RBM10, as well as other splicing regulators. [82] Studies on such networks are expected to promote our understanding of transcriptomic homeostasis regulated by splicing and the molecular and biological significance of RBM10 in cells.

RBM10 regulates hundreds of genes. [9] [10] [13] [14] [15] Further studies on the various RBM10-mediated processes and pathways may help elucidate the pathogenesis and progression of diseases caused by RBM10 mutations and the mechanisms of the antithetical actions of RBM10 as a tumor suppressor, and in certain cases, a tumor promoter, and provide clues for better treatment of the diseases.

Notes

Related Research Articles

<span class="mw-page-title-main">RNA splicing</span> Process in molecular biology

RNA splicing is a process in molecular biology where a newly-made precursor messenger RNA (pre-mRNA) transcript is transformed into a mature messenger RNA (mRNA). It works by removing all the introns and splicing back together exons. For nuclear-encoded genes, splicing occurs in the nucleus either during or immediately after transcription. For those eukaryotic genes that contain introns, splicing is usually needed to create an mRNA molecule that can be translated into protein. For many eukaryotic introns, splicing occurs in a series of reactions which are catalyzed by the spliceosome, a complex of small nuclear ribonucleoproteins (snRNPs). There exist self-splicing introns, that is, ribozymes that can catalyze their own excision from their parent RNA molecule. The process of transcription, splicing and translation is called gene expression, the central dogma of molecular biology.

<span class="mw-page-title-main">Alternative splicing</span> Process by which a gene can code for multiple proteins

Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be included within or excluded from the final, processed messenger RNA (mRNA) produced from that gene. This means the exons are joined in different combinations, leading to different (alternative) mRNA strands. Consequently, the proteins translated from alternatively spliced mRNAs usually contain differences in their amino acid sequence and, often, in their biological functions.

<span class="mw-page-title-main">Protein isoform</span> Forms of a protein produced from different genes

A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have unique functions. A set of protein isoforms may be formed from alternative splicings, variable promoter usage, or other post-transcriptional modifications of a single gene; post-translational modifications are generally not considered. Through RNA splicing mechanisms, mRNA has the ability to select different protein-coding segments (exons) of a gene, or even different parts of exons from RNA to form different mRNA sequences. Each unique sequence produces a specific form of a protein.

<span class="mw-page-title-main">Clusterin</span> Protein-coding gene in the species Homo sapiens

Clusterin is a 75-80 kDa disulfide-linked heterodimeric protein associated with the clearance of cellular debris and apoptosis. In humans, clusterin is encoded by the CLU gene on chromosome 8. CLU is a molecular chaperone responsible for aiding protein folding of secreted proteins, and its three isoforms have been differentially implicated in pro- or antiapoptotic processes. Through this function, CLU is involved in many diseases related to oxidative stress, including neurodegenerative diseases, cancers, inflammatory diseases, and aging.

<span class="mw-page-title-main">L1 (protein)</span> Mammalian protein found in Homo sapiens

L1, also known as L1CAM, is a transmembrane protein member of the L1 protein family, encoded by the L1CAM gene. This protein, of 200-220 kDa, is a neuronal cell adhesion molecule with a strong implication in cell migration, adhesion, neurite outgrowth, myelination and neuronal differentiation. It also plays a key role in treatment-resistant cancers due to its function. It was first identified in 1984 by M. Schachner who found the protein in post-mitotic mice neurons.

<span class="mw-page-title-main">Tropomyosin</span> Protein

Tropomyosin is a two-stranded alpha-helical, coiled coil protein found in many animal and fungal cells. In animals, it is an important component of the muscular system which works in conjunction with troponin to regulate muscle contraction. It is present in smooth and striated muscle tissues, which can be found in various organs and body systems, including the heart, blood vessels, respiratory system, and digestive system. In fungi, tropomyosin is found in cell walls and helps maintain the structural integrity of cells.

RNA-binding proteins are proteins that bind to the double or single stranded RNA in cells and participate in forming ribonucleoprotein complexes. RBPs contain various structural motifs, such as RNA recognition motif (RRM), dsRNA binding domain, zinc finger and others. They are cytoplasmic and nuclear proteins. However, since most mature RNA is exported from the nucleus relatively quickly, most RBPs in the nucleus exist as complexes of protein and pre-mRNA called heterogeneous ribonucleoprotein particles (hnRNPs). RBPs have crucial roles in various cellular processes such as: cellular function, transport and localization. They especially play a major role in post-transcriptional control of RNAs, such as: splicing, polyadenylation, mRNA stabilization, mRNA localization and translation. Eukaryotic cells express diverse RBPs with unique RNA-binding activity and protein–protein interaction. According to the Eukaryotic RBP Database (EuRBPDB), there are 2961 genes encoding RBPs in humans. During evolution, the diversity of RBPs greatly increased with the increase in the number of introns. Diversity enabled eukaryotic cells to utilize RNA exons in various arrangements, giving rise to a unique RNP (ribonucleoprotein) for each RNA. Although RBPs have a crucial role in post-transcriptional regulation in gene expression, relatively few RBPs have been studied systematically.It has now become clear that RNA–RBP interactions play important roles in many biological processes among organisms.

<span class="mw-page-title-main">T-box transcription factor T</span> Protein-coding gene in the species Homo sapiens

T-box transcription factor T, also known as Brachyury protein, is encoded for in humans by the TBXT gene. Brachyury functions as a transcription factor within the T-box family of genes. Brachyury homologs have been found in all bilaterian animals that have been screened, as well as the freshwater cnidarian Hydra.

<span class="mw-page-title-main">PAX3</span> Paired box gene 3

The PAX3 gene encodes a member of the paired box or PAX family of transcription factors. The PAX family consists of nine human (PAX1-PAX9) and nine mouse (Pax1-Pax9) members arranged into four subfamilies. Human PAX3 and mouse Pax3 are present in a subfamily along with the highly homologous human PAX7 and mouse Pax7 genes. The human PAX3 gene is located in the 2q36.1 chromosomal region, and contains 10 exons within a 100 kb region.

<span class="mw-page-title-main">Neurofibromin 1</span> Mammalian protein found in Homo sapiens

neurofibromatosis 1 (NF1) is a gene in humans that is located on chromosome 17. NF1 codes for neurofibromin, a GTPase-activating protein that negatively regulates RAS/MAPK pathway activity by accelerating the hydrolysis of Ras-bound GTP. NF1 has a high mutation rate and mutations in NF1 can alter cellular growth control, and neural development, resulting in neurofibromatosis type 1. Symptoms of NF1 include disfiguring cutaneous neurofibromas (CNF), café au lait pigment spots, plexiform neurofibromas (PN), skeletal defects, optic nerve gliomas, life-threatening malignant peripheral nerve sheath tumors (MPNST), pheochromocytoma, attention deficits, learning deficits and other cognitive disabilities.

p16 Mammalian protein found in Homo sapiens

p16, is a protein that slows cell division by slowing the progression of the cell cycle from the G1 phase to the S phase, thereby acting as a tumor suppressor. It is encoded by the CDKN2A gene. A deletion in this gene can result in insufficient or non-functional p16, accelerating the cell cycle and resulting in many types of cancer.

<span class="mw-page-title-main">TP63</span> Protein-coding gene in the species Homo sapiens

Tumor protein p63, typically referred to as p63, also known as transformation-related protein 63 is a protein that in humans is encoded by the TP63 gene.

<span class="mw-page-title-main">TIA1</span> Mammalian protein found in Homo sapiens

TIA1 or Tia1 cytotoxic granule-associated rna binding protein is a 3'UTR mRNA binding protein that can bind the 5'TOP sequence of 5'TOP mRNAs. It is associated with programmed cell death (apoptosis) and regulates alternative splicing of the gene encoding the Fas receptor, an apoptosis-promoting protein. Under stress conditions, TIA1 localizes to cellular RNA-protein conglomerations called stress granules. It is encoded by the TIA1 gene.

<span class="mw-page-title-main">Wilms tumor protein</span> Transcription factor gene involved in the urogenital system

Wilms tumor protein (WT33) is a protein that in humans is encoded by the WT1 gene on chromosome 11p.

<span class="mw-page-title-main">HNRNPA2B1</span> Protein-coding gene in the species Homo sapiens

Heterogeneous nuclear ribonucleoproteins A2/B1 is a protein that in humans is encoded by the HNRNPA2B1 gene.

<span class="mw-page-title-main">STK11</span> Protein-coding gene in the species Homo sapiens

Serine/threonine kinase 11 (STK11) also known as liver kinase B1 (LKB1) or renal carcinoma antigen NY-REN-19 is a protein kinase that in humans is encoded by the STK11 gene.

<span class="mw-page-title-main">RBM4</span> Protein-coding gene in the species Homo sapiens

RNA-binding protein 4 is a protein that in humans is encoded by the RBM4 gene.

<span class="mw-page-title-main">EIF4A3</span> Protein-coding gene in the species Homo sapiens

Eukaryotic initiation factor 4A-III is a protein that in humans is encoded by the EIF4A3 gene.

<span class="mw-page-title-main">MALAT1</span>

MALAT 1 also known as NEAT2 is a large, infrequently spliced non-coding RNA, which is highly conserved amongst mammals and highly expressed in the nucleus. MALAT1 was identified in multiple types of physiological processes, such as alternative splicing, nuclear organization, epigenetic modulating of gene expression, and a number of evidences indicate that MALAT1 also closely relate to various pathological processes, ranging from diabetes complications to cancers. It regulates the expression of metastasis-associated genes. It also positively regulates cell motility via the transcriptional and/or post-transcriptional regulation of motility-related genes. MALAT1 may play a role in temperature-dependent sex determination in the Red-eared slider turtle.

<span class="mw-page-title-main">Minigene</span>

A minigene is a minimal gene fragment that includes an exon and the control regions necessary for the gene to express itself in the same way as a wild type gene fragment. This is a minigene in its most basic sense. More complex minigenes can be constructed containing multiple exons and intron(s). Minigenes provide a valuable tool for researchers evaluating splicing patterns both in vivo and in vitro biochemically assessed experiments. Specifically, minigenes are used as splice reporter vectors and act as a probe to determine which factors are important in splicing outcomes. They can be constructed to test the way both cis-regulatory elements and trans-regulatory elements affect gene expression.

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