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Results for “Alternative Splicing”

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PubMed1999

Two mRNA species encoding calcium-dependent protein kinases are differentially expressed in sexual organs of Marchantia polymorpha through alternative splicing.

In plants, calcium-dependent calmodulin-independent protein kinases (CDPKs) are the predominant calcium-regulated protein kinases and their genes are encoded by a multigene family. A CDPK gene was cloned from a liverwort, Marchantia polymorpha, which showed a high level of sequence similarities to other higher plant CDPK genes. The liverwort CDPK gene consisted of 9 exons and 8 introns. The 6th and 7th exons (Exon 6A and Exon 6B) were almost identical except for 4-amino acid substitutions, both of which coded for EF-hands in the calcium-binding domain. RT-PCR analysis revealed that two species of mature mRNA containing either Exon 6A or Exon 6B were generated from a single CDPK gene by mutually exclusive alternative splicing. Both histidine-tagged fusion proteins derived from cDNAs containing either Exon 6A or Exon 6B exhibited calcium-dependent protein kinase activity in vitro. Preferential accumulation of the mature mRNA with Exon 6A detected in male sexual organ implies possible sexual control of the ratio between the two CDPK isozymes through alternative splicing. Functions and evolution of CDPKs are discussed based on the structure and expression of the liverwort CDPK gene.

Alternative Splicing↗

PubMed2002

Mouse heart Na+ channels: primary structure and function of two isoforms and alternatively spliced variants.

We isolated two full-length cDNA clones from the adult murine heart that encode two different voltage-gated Na+ channels: mH1 and mH2. Sequence comparisons indicated that mH1 is highly homologous to rat SCN5A, whereas mH2 is highly homologous to SCN4A, expressed in rat skeletal muscle. Electrophysiological properties of mH1 channels strongly resembled the tetrodotoxin (TTX)-resistant Na+ current of mouse ventricular cells, whereas mH2 channels activated at more positive potentials and were highly sensitive to TTX [50% inhibitory constant (IC50) = 11 nM]. We found that mH2 is not expressed in cardiac cells of neonatal mice, but appears to be upregulated during the development. Besides these Na+ channel isoforms, we also detected two alternatively spliced mH1 variants that were characterized by deletions within the sequence coding for the intracellular loop between domains II and III. One of the shortened channels, mH1-2, developed Na+ currents indistinguishable from those of mH1. The other splice variant (mH1-3) did not form functional channels. Quantitative reverse transcriptase-polymerase chain reaction indicated that RNA preparations of the adult mouse heart contain 54% mH1, 25% mH1-2, 16% mH2, and 5% mH1-3. Conclusively, mH1 generates the main portion of the mouse cardiac TTX-resistant Na+ current and mH2 is a candidate for TTX-sensitive currents previously described in adult cardiomyocytes. Furthermore, the presence of mH1-2 and mH1-3 transcripts indicates that alternative splicing plays a role in the regulation of functional Na+ channels in cardiomyocytes.

Alternative Splicing↗

PubMed1999

Regulation of fibronectin EDA exon alternative splicing: possible role of RNA secondary structure for enhancer display.

The fibronectin primary transcript undergoes alternative splicing in three noncoordinated sites: the cassette-type EDA and EDB exons and the more complex IIICS region. We have shown previously that an 81-nucleotide region within the EDA exon is necessary for exon recognition and that this region contains at least two splicing-regulatory elements: a polypurinic enhancer (exonic splicing enhancer [ESE]) and a nearby silencer element (exonic splicing silencer [ESS]). Here, we have analyzed the function of both elements in different cell types. We have mapped the ESS to the nucleotide level, showing that a single base change is sufficient to abolish its function. Testing of the ESE and ESS elements in heterologous exons, individually or as part of the complete EDA regulatory region, showed that only the ESE element is active in different contexts. Functional studies coupled to secondary-structure enzymatic analysis of the EDA exon sequence variants suggest that the role of the ESS element may be exclusively to ensure the proper RNA conformation and raise the possibility that the display of the ESE element in a loop position may represent a significant feature of the exon splicing-regulatory region.

Alternative Splicing↗

PubMed1994

Processing, axonal transport and cardioregulatory functions of peptides derived from two related prohormones generated by alternative splicing of a single gene in identified neurons VD1 and RPD2 of Lymnaea.

The VD1/RPD2 mRNA precursor in identified neurons VD1 and RPD2 of the freshwater snail Lymnaea stagnalis is alternatively spliced to yield two related variants encoding two distinct yet related preprohormones, named the VD1/RPD2-A and -B preprohormones. Here, we report the isolation and structural characterization of alpha 1, alpha 2 and beta peptides from dissected neurons VD1 and RPD2. The alpha 1 and alpha 2 peptides are derived from VD1/RPD2-A and B prohormones, respectively, whereas beta peptide is identical for both prohormones. In addition, we report the isolation and structural characterization of the alpha 2 peptide from the heart, demonstrating that the mature peptides are transported and released in the heart. The pharmacological actions of synthetic alpha 1 and alpha 2 peptides on isolated auricle preparations of the Lymnaea heart were examined. The two alpha peptides have similar excitatory effects on beat rate and beat amplitude, while their potencies differed considerably, indicating that alternative splicing results in structurally and functionally overlapping, through non-identical, sets of peptides.

Amino Acid Sequence↗

PubMed1994

A novel POU domain gene, zebrafish pou2: expression and roles of two alternatively spliced twin products in early development.

POU domain proteins are a large family of transcriptional regulatory proteins, many of which are implicated in the control of gene expression during early development. We describe here the cloning and expression of zebrafish pou2, a novel POU domain gene related to the mouse germ-line-specific transcription factor oct-3. Zebrafish pou2 is maternally expressed, and the transcripts are present from the one-cell stage to the gastrula stage. In situ hybridization analyses revealed that the transcripts were present in all blastomeres until the midblastula stage and that the expression was restricted to the epiblast during gastrulation. We found that alternatively spliced transcripts, t-pou2 RNAs, were also expressed in the embryos. In contrast to the Pou2 product, the t-Pou2 product lacks DNA-binding activity because of its incomplete POU domain structure. To examine the roles of the Pou2 and t-Pou2 products, we increased their expression in the embryo by microinjection of synthetic pou2 and t-pou2 RNAs into the fertilized eggs at the one-cell stage. Most embryos that developed from the eggs injected with pou2 RNA did not show any obvious developmental defects. In contrast, overexpression of the t-Pou2 product greatly affected the embryonic development: There was strong developmental retardation or arrest due to the incomplete gastrulation. In the affected embryos, expression of zebrafish T gene was reduced and the hypoblast formation was disturbed. Temporal and spatial expression patterns and the effects of overexpression of these products on development are consistent with the idea that the Pou2 and t-Pou2 proteins are involved in early development of zebrafish embryos. They may be involved in the proliferation of blastomeres in undetermined state at the blastula stage and/or the early cell commitment events at the gastrula stage. Also, our results indicate that different products generated as a result of alternative splicing from the same gene possess distinct functional capacities.

Alternative Splicing↗

PubMed1993

Genetic identification, sequence, and alternative splicing of the Caenorhabditis elegans alpha 2(IV) collagen gene.

The nematode Caenorhabditis elegans has two type IV collagen genes homologous to the mammalian alpha 1(IV) and alpha 2(IV) collagen genes. We demonstrate by transgenic rescue of mutant animals that the genetic locus encoding the C. elegans alpha 2(IV) collagen gene is let-2 on the X chromosome. The most severe effect of mutations in let-2 is temperature-sensitive embryonic lethality. The embryonic lethal phenotype is similar to that seen in animals with mutations in the alpha 1(IV) collagen gene, emb-9. The sequence of the entire C. elegans alpha 2(IV) collagen gene is presented. Comparisons with mammalian type IV collagen sequences show high amino acid sequence conservation in the C-terminal NCl domain and of crosslinking residues (Cys and Lys) in the N-terminal 7S domain. RT-PCR analysis shows that transcripts of the C. elegans alpha 2(IV) collagen gene are alternatively spliced. Transcripts contain one of two mutually exclusive exons, exon 9 or 10. These exons encode very similar products, differing primarily in the sequence of a 9-10 amino acid Gly-X-Y interruption. The expression of these alternatively spliced alpha 2(IV) collagen transcripts is developmentally regulated. In embryos over 90% of the alpha 2(IV) collagen mRNA contains exon 9, while larval and adult RNAs contain 80-90% exon 10. This shift in expression of alternative alpha 2(IV) collagen transcripts suggests that C. elegans embryos may require a different form of alpha 2(IV) collagen than do larvae and adults.

Alternative Splicing↗

PubMed1996

Relief of ornithine decarboxylase messenger RNA translational repression induced by alternative splicing of its 5' untranslated region.

The ornithine decarboxylase enzyme (ODC) is the key regulator of polyamine synthesis and is a member of the cellular proto-oncogene family. Its expression becomes constitutively activated by carcinogens, viruses, and oncogenes. ODC mRNA has a long 5' untranslated region that could be important in the regulation of enzyme levels by affecting translation. To test this hypothesis, we have determined the role of this region on the constitutive ODC hyperexpression measured in AR4-2J cells, an azaserine-induced, tumor-derived pancreatic acinar cell line. Construction of expression vectors in which ODC 5' leader sequence was placed flanking the chloramphenicol acetyltransferase reporter gene allowed us to identify three AR4-2J specific, different alternatively spliced ODC 5' leaders. The 5' ends of exons 2 and 3 were lengthened by 17 and 13 bases, respectively. Translation performed in a cell-free system as well as in COS7 transient transfection experiments demonstrated that AR4-2J isoforms induce a strong increase in the rate of translation. These results provide evidence that alternative splicing observed in tumoral cells, coupled with translation regulation, relieves the translation repression mediated by the long and structured 5' untranslated region of the ODC proto-oncogene.

Alternative Splicing↗

PubMed2006

Differential regulation of transcript accumulation and alternative splicing of a DREB2 homolog under abiotic stress conditions in common wheat.

A number of cold responsive (Cor)/late embryogenesis abundant (Lea) genes are induced by both low temperature (LT) and dehydration. To understand the molecular basis of cold acclimation and its relationship with drought stress response in wheat seedlings, we isolated a DREB2 homolog Wdreb2, which is the candidate gene for a transcription factor of the Cor/Lea genes. The Wdreb2 expression was activated by cold, drought, salt and exogenous ABA treatment. Detailed expression studies of Wdreb2 indicated the involvement of two distinct pathways of its activation, a drought and salt stress-responsive pathway and a cold-responsive pathway. The transient expression analysis showed that the Wrab19 expression was directly activated by the WDREB2 transcription factor in wheat cells. Three transcript forms of Wdreb2 (Wdreb2alpha, Wdreb2beta and Wdreb2gamma) were produced through alternative splicing. Under drought and salt stress conditions, the amount of the Wdreb2beta form remained fairly constant during 24-hour treatment, while those of the Wdreb2alpha and Wdreb2gamma forms showed transient increases. On the other hand, the LT treatment resulted in increased transcript levels of all three forms of Wdreb2. Thus, under the LT and drought/salt stress conditions the amount of the WDREB2 transcription factors in wheat is differentially controlled by the level of transcription and alternative splicing.

Abscisic Acid↗

PubMed1998

Genetic polymorphisms and alternative splicing of the hOGG1 gene, that is involved in the repair of 8-hydroxyguanine in damaged DNA.

The hOGG1 gene encodes a DNA glycosylase that excises 8-hydroxyguanine (oh8Gua) from damaged DNA. Structural analyses of the hOGG1 gene and its transcripts were performed in normal and lung cancer cells. Due to a genetic polymorphism at codon 326, hOGG1-Ser326 and hOGG1-Cys326 proteins were produced in human cells. Activity in the repair of oh8Gua was greater in hOGG1-Ser326 protein than in hOGG1-Cys326 protein in the complementation assay of an E. coli mutant defective in the repair of oh8Gua. Two isoforms of hOGG1 transcripts produced by alternative splicing encoded distinct hOGG1 proteins: one with and the other without a putative nuclear localization signal. Loss of heterozygosity at the hOGG1 locus was frequently (15/ 23, 62.2%) detected in lung cancer cells, and a cell line NCI-H526 had a mutation leading to the formation of the transcripts encoding a truncated hOGG1 protein. However, the oh8Gua levels in nuclear DNA were similar among lung cancer cells and leukocytes irrespective of the type of hOGG1 proteins expressed. These results suggest that the oh8Gua levels are maintained at a steady level, even though multiple hOGG1 proteins are produced due to genetic polymorphisms, mutations and alternative splicing of the hOGG1 gene.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed1999

Family of prohormone convertases in Lymnaea: characterization of two alternatively spliced furin-like transcripts and cell-specific regulation of their expression.

The majority of neuropeptides in Lymnaea stagnalis are proteolytically processed from larger precursors at sites composed of single or multiple basic amino acid residues. Previous studies have identified several putative prohormone convertases in the brain of Lymnaea. To characterize the complete family, we undertook three independent approaches: reverse-transcribed polymerase chain reaction screening, and low-stringency cDNA and genomic library screenings. The central nervous system cDNA library screening yielded two cDNAs encoding Lfurin1 and its variant form, Lfurin1-X. Both proteins show the characteristic organization of (human) furin with a putative catalytic domain, a P domain, a Cys-rich domain, a transmembrane domain, and a cytoplasmic tail. Lfurin1 and Lfurin1-X are identical, apart from a putative alternatively spliced noncatalytic luminal protein domain, which is present exclusively in Lfurin1-X. In situ hybridization revealed that the Lfur1 gene is expressed throughout the Lymnaea brain, but that the level varies considerably from one neuron to another. Quantitative analysis of the expression level of the two alternatively spliced transcripts revealed that it is neuron type-specifically regulated. This probably indicates the functional importance of noncatalytic luminal protein domains in these enzymes. In addition, our findings suggest that apart from the identified convertases LPC2, Lfurin1/Lfurin1-X, and Lfurin2, additional prohormone convertase diversity is either not present or present only at low levels in the Lymnaea brain. Alternatively, additional prohormone convertases could exist with a lower degree of sequence conservation than the other Lymnaea prohormone convertase members. From our findings, it appears that the majority of prohormone processing in Lymnaea is carried out by the three thus far identified types of Kex2-related prohormone convertases despite the large number of neuropeptide precursors and diverse multiple basic cleavage sites hydrolyzed.

Alternative Splicing↗

PubMed2006

Alternative splicing in protein associated with Myc (Pam) influences its binding to c-Myc.

We recently identified Pam (for protein associated with c-Myc), as a binding partner for the tuberous sclerosis complex (TSC) protein tuberin in brain. The highly conserved Pam homologs in Drosophila and C. elegans are neuron-specific proteins that regulate synaptic growth. The Pam gene contains 83 exons and encodes a 4,641-amino-acid polypeptide with a predicted molecular weight of approximately 510 kDa. In a previous study, we demonstrated that Pam is expressed as two forms, approximately 450 kDa in rat embryonic and a approximately 350 kDa in rat adult brain. Here we have extended that work to show the approximately 450 kDa form is expressed in rat embryonic kidney, heart, and lung and in rat cell lines, and the approximately 350 kDa form is expressed in adult rat tissues as well as in human and mouse brain and human and mouse cell lines. To understand the size difference, we investigated alternative splicing of Pam in brain and detected six isoforms in the Myc-binding region resulting from splicing of exon 53, and three new exons, 52A, 56, and 56A. We also demonstrate that the presence of exon 52A in Pam significantly enhances binding to Myc, suggesting functional importance of this alternative splicing. The presence of Pam in many cellular compartments, its spliced variants, as well as its multiple binding partners, including tuberin, make it a complex, yet intriguing protein in the nervous system.

Alternative Splicing↗

PubMed1994

Identification of a complete Cek7 receptor protein tyrosine kinase coding sequence and cDNAs of alternatively spliced transcripts.

Receptor protein tyrosine kinases (RPTK) are critical components of signal transduction pathways in multicellular organisms. Identification of new RPTK constitutes an initial step in understanding the variety of signalling pathways in which these proteins participate. In this study, a cDNA containing a complete coding sequence for Cek7 (chicken RPTK) has been cloned from a chicken embryo expression library using anti-phosphotyrosine antibodies (Ab). Cek7 is a member of the EPH (human RPTK) subfamily of RPTK; this subfamily is characterized by extracellular domains containing an immunoglobulin-like motif, a Cys-rich region and two fibronectin type-III repeats. Analysis of additional cDNAs revealed that two positions of alternative splicing in primary transcripts may produce several isoforms of this RPTK; cDNAs corresponding to three isoforms of this receptor are reported. These isoforms are predicted to have altered extracellular ligand-binding domains and/or altered cytoplasmic juxtamembrane regions. The nucleotide sequence of cek7 cDNAs identified in this study diverges at the 3' end from the sequence found in a recently described partial cek7 cDNA [Sajjadi and Pasquale, Oncogene 8 (1993) 1807-1813]. Therefore, a third position of alternative splicing may produce Cek7 RPTK with divergent C-terminal tails. RNA blot analysis revealed expression of this receptor at highest levels in the central nervous system and eyes of 10-day-old chicken embryos.

Alternative Splicing↗

PubMed2006

Intron retention as an alternative splice variant of the rat urocortin 1 gene.

Urocortin 1, highly conserved metazoan gene of the corticotropin-releasing hormone family, is a simple gene structured in two exons and the corresponding intron. The urocortin 1 prepropeptide is entirely coded in the second exon. Preliminary non-isotopic in situ hybridization experiments with an oligonucleotide complementary to an intron sequence of the urocortin 1 gene showed a significant cytoplasmic-like staining, suggesting the occurrence of an intron-retained urocortin 1 transcript. This observation prompted us to study whether the urocortin 1 gene presents alternative splicing by intron retention event. Confocal fluorescent in situ hybridization for urocortin 1 RNA and the use of the specific DNA dye TOPRO-3 allowed us to show significant expression of the intron-retained urocortin 1 transcript that did not colocalize with TOPRO-3 staining indicating a cytoplasmic localization for the intron-retained urocortin 1 transcript. The natural occurrence of a polyadenylated intron-retained urocortin 1 RNA was further documented by reverse transcriptase polymerase chain reaction (PCR), primed with oligo(dT), of total RNA extracted from three brain regions, a midbrain region containing the Edinger-Westphal nucleus, cerebellum and prefrontal cortex. In the three brain regions studied, it was possible to amplify both intron-less as well as intron-retained urocortin 1 transcripts. The use of PCR primers that simultaneously amplify both urocortin 1 transcripts allowed us to show that the expression of both urocortin 1 transcripts differs among the brain regions analyzed, suggesting a tissue specific regulation of this alternative splicing. In silico analysis of the five known mammalian urocortin 1 genomic sequences showed high conservation of the urocortin 1 intron sequence. Further studies should investigate the regulation of this intron retention event and its consequence for the functionality of the urocortin 1 gene.

Alternative Splicing↗

PubMed1997

Long and short forms of the ovine prolactin receptor: cDNA cloning and genomic analysis reveal that the two forms arise by different alternative splicing mechanisms in ruminants and in rodents.

Prolactin is a pituitary hormone that binds to specific receptors in numerous tissues. Depending on the size of their cytoplasmic domain, long and short prolactin receptors (l-PR, s-PR) have been described. Up to now, s-PR were found in rodents only. We report here the cloning of full-length coding sequences for short and long ovine prolactin receptors (s-oPR, l-oPR). The only difference between s- and l-oPR coding sequences was, respectively, the presence or absence of a 39 base pair insert at the beginning of the cytoplasmic domain, with two contiguous inframe stop codons at its 3' end. Sequence comparison revealed that the alternative splicing producing s- and l-oPR was different from that of rodents, although the resulting proteins were very similar. PCR experiments on ovine genomic DNA showed that the 39 base pair insert was directly linked to the downstream exon, and separated from the upstream exon by an 800 base pair intron. Thus, the alternative splicing used a single intron with one 5' and two 3' sites. The same organization was found in bovine and caprine genomes, suggesting that this feature is general in ruminants and different from rodents, which use mutually exclusive exons to produce s-PR and l-PR.

Alternative Splicing↗

PubMed1999

Alternative splicing of the telomerase catalytic subunit in human oocytes and embryos.

The human telomerase catalytic subunit (hTCS) is a ribonucleoprotein which synthesizes telomere repeats on the ends of chromosomes. Telomerase activity is thought to be essential in maintaining normal telomere length in immortal (cancer) and germ cells. The objective of this study was to determine the gene expression of telomerase mRNA in human oocytes at different meiotic stages and in embryos. Normal and abnormal human oocytes, preimplantation embryos, and blastocysts were analysed for the presence and expression of the hTCS transcripts. Multiple telomerase mRNA products were identified by reverse transcription-polymerase chain reaction (RT-PCR) using primers within the reverse transcriptase domain. DNA sequencing of these amplicons suggest that there are alternative splicing variants which align to other telomerase reverse transcriptase (RT) consensus domains. Surprisingly, in unfertilized and immature gametes, as well as preimplantation embryos, hTCS expression revealed three different PCR product sizes, 457, 421 and 275 bp. The frequency of the 275 bp DNA product was 6.6% in oocytes (two out of 30) compared with 56.6% (17 out of 30) in poorly developing human preimplantation embryos (P < 0.005). The presence of alternately spliced mRNA variants in human preimplantation embryos may suggest a lack of telomerase activity and thus chromosomes associated with shortened telomeres.

Alternative Splicing↗

PubMed1991

An alternatively spliced c-mil/raf mRNA is predominantly expressed in chicken muscular tissues and conserved among vertebrate species.

The chicken c-mil gene produces two mRNA species generated by an alternative splicing mechanism. These two transcripts differ at least by the presence or absence of a 60 nucleotide exon (E7a) localized at the splice junction of c-mil exons 7 and 8. By using RNAase protection assays, we have analysed the pattern of expression of these two mRNA species in several chicken tissues. Here we report that the two c-mil mRNAs are differentially expressed in chicken tissues: the mRNA lacking E7a is detected in all tissues tested, while the mRNA containing E7a is detected only in the skeletal muscle, heart and brain. Sequences homologous to E7a have also been detected in DNAs from quail, mouse and human cells and their sequencing revealed that the alternative E7a is structurally preserved in these species. By PCR analyses performed on RNAs extracted from muscular tissues of these species, we also show that the alternative splicing mechanism described in chicken also occurs in these species.

Amino Acid Sequence↗

PubMed1999

Myeloma cells release soluble interleukin-6Ralpha in relation to disease progression by two distinct mechanisms: alternative splicing and proteolytic cleavage.

Multiple myeloma (MM) is a plasma-cell malignancy characterized by the accumulation of malignant plasma cells within the bone marrow. Interleukin (IL)-6 is an essential survival and growth factor for myeloma cells that exerts its activity through a cell surface receptor composed of an 80-kDa ligand binding molecule (IL-6Ralpha) and a 130-kDa signal-transducing molecule. Of major interest, the soluble form of the IL-6Ralpha (sIL-6Ralpha) is an agonistic molecule able to potentiate IL-6 activity and a strong prognostic factor in MM. In the present study, we demonstrate that purified myeloma cells from all of the patients with MM and human myeloma cell lines release sIL-6Ralpha. The level of sIL-6Ralpha release correlates with disease activity and is clearly up-regulated during tumoral expansion in vivo and immortalization in vitro. Of note, this sIL-6Ralpha release is strongly reduced (50%) by a hydroxamate-based metalloproteinase inhibitor underlying the importance of shedding in the production of sIL-6Ralpha by myeloma cells. Using specific IL-6Ralpha primers flanking the transmembrane domain, we demonstrate by PCR the presence of two IL-6R mRNAs corresponding to the membrane IL-6Ralpha and to the sIL-6Ralpha generated through alternative splicing in myeloma cells. In conclusion, we show that: (a) native myeloma cells and human myeloma cell lines release sIL-6Ralpha by two distinct mechanisms: alternative splicing and proteolytic cleavage of the membrane IL-6Ralpha; and (b) the release of the sIL-6Ralpha, which is an agonist of IL-6, correlates with disease progression, explaining in part its strong prognostic value in vivo.

Alternative Splicing↗

PubMed2004

Alternative splicing generates an isoform of the human Sef gene with altered subcellular localization and specificity.

Receptor tyrosine kinases (RTKs) control a multitude of biological processes and are therefore subjected to multiple levels of regulation. Negative feedback is one of the mechanisms that provide an effective means to control RTK-mediated signaling. Sef has recently been identified as a specific antagonist of fibroblast growth factor (FGF) signaling in zebrafish and subsequently in mouse and human. Sef encodes a putative type I transmembrane protein that antagonizes the Ras/mitogen-activated protein kinase pathway in all three species. Mouse Sef was also shown to inhibit the phosphatidylinositol 3-kinase pathway. We show here that an alternative splicing mechanism generates an isoform of human Sef, hSef-b, which unlike the previously reported Sef (hSef-a) is a cytosolic protein. Contrary to hSef-a, which is ubiquitously expressed, hSef-b transcripts display a restricted pattern of expression in human tissues. hSef-b inhibits FGF-induced cell proliferation and prevents the activation of mitogen-activated protein kinase without affecting the upstream component MAPK kinase. Furthermore, hSef-b does not antagonize FGF induction of the phosphatidylinositol 3-kinase pathway. In addition to the effects on FGF signaling, hSef-b inhibited cellular response to platelet-derived growth factor but not other RTK ligands. Therefore, alternative splicing of the hSef gene expands the Sef feedback inhibition repertoire of RTK signaling.

Alternative Splicing↗