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Query: UNIPROT:P06889 (Mol)
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Eph, Elk, and Eck are prototypes of a large family of transmembrane protein-tyrosine kinases, which are characterized by a highly conserved cysteine-rich domain and two fibronectin type III repeats in their extracellular regions. Despite the extent of the Eph family, no extracellular ligands for any family member have been identified, and hence, little is known about the biological and biochemical properties of these receptor-like tyrosine kinases. In the absence of a physiological ligand for the Elk receptor, we constructed chimeric receptor molecules, in which the extracellular region of the Elk receptor is replaced by the extracellular, ligand-binding domain of the epidermal growth factor (EGF) receptor. These chimeric receptors were expressed in NIH 3T3 cells that lack endogenous EGF receptors to analyze their signaling properties. The chimeric EGF-Elk receptors became glycosylated, were correctly localized to the plasma membrane, and bound EGF with high affinity. The chimeric receptors underwent autophosphorylation and induced the tyrosine phosphorylation of a specific set of cellular proteins in response to EGF. EGF stimulation also induced DNA synthesis in fibroblasts stably expressing the EGF-Elk receptors. In contrast, EGF stimulation of these cells did not lead to visible changes in cellular morphology, nor did it induce loss of contact inhibition in confluent monolayers or growth in semisolid media. The Elk cytoplasmic domain is therefore able to induce tyrosine phosphorylation and DNA synthesis in response to an extracellular ligand, suggesting that Elk and related polypeptides function as ligand-dependent receptor tyrosine kinases.
Mol Cell Biol 1993 Nov
PMID:Biological and biochemical activities of a chimeric epidermal growth factor-Elk receptor tyrosine kinase. 841 96

We describe our characterization of kin-15 and kin-16, a tandem pair of homologous Caenorhabditis elegans genes encoding transmembrane protein tyrosine kinases (PTKs) with an unusual structure: the predicted extracellular domain of each putative gene product is only about 50 amino acids, and there are no potential autophosphorylation sites in the C-terminal domain. Using lacZ fusions, we found that kin-15 and kin-16 both appear to be expressed during postembryonic development in the large hypodermal syncytium (hyp7) around the time that specific hypodermal cells fuse with hyp7. kin-15 and kin-16 were positioned on the genetic and physical maps, but extrachromosomal arrays containing wild-type kin-15 and/or kin-16 genes were unable to complement candidate lethal mutations. The results suggest that kin-15 and kin-16 may be specifically involved in cell-cell interactions regulating cell fusions that generate the hypodermis during postembryonic development.
Mol Cell Biol 1993 Nov
PMID:Two novel transmembrane protein tyrosine kinases expressed during Caenorhabditis elegans hypodermal development. 841 2

The visual pigment which serves as the first step in the phototransduction cycle in vertebrate rod cells consists of a retinal chromophore which is linked to the transmembrane protein, opsin. Opsin genes have been isolated from a number of different organisms and studies have shown opsin to be developmentally regulated with both mRNA and protein expression associated with the morphological differentiation of photoreceptor cells. Due to its potential utility as a marker for rod photoreceptor determination in studies of retinal tissue interactions, and because no amphibian opsin genes have as yet been cloned, we isolated cDNA clones of the Xenopus laevis opsin gene. Sequence analysis shows that within the coding region Xenopus opsin shares a high degree of identity with other rod opsin genes, except at the C-terminal where it more closely resembles the mammalian color opsins. A developmental analysis, on the other hand, reveals that Xenopus opsin transcripts are detectable in a retina-specific fashion early in retinal development. Using in situ hybridization we find that Xenopus opsin mRNA is initially restricted to a few isolated cells in the presumptive photoreceptor layer which express the gene at relatively high levels. This suggests that rod photoreceptor determination occurs in single cells, and that the mechanisms controlling opsin expression in Xenopus are initiated well before any evidence of morphological differentiation.
Brain Res Mol Brain Res 1993 Mar
PMID:Early opsin expression in Xenopus embryos precedes photoreceptor differentiation. 851 May 3

Penetration into the brain is an important consideration in the pharmacological use of neurotrophic factors for the treatment of brain neurodegeneration, e.g., in Alzheimer's disease. Furthermore, intracerebroventricular treatment with nerve growth factor (NGF) has been found to induce side effects, including aberrant sympathetic sprouting and weight loss. Such findings suggest that direct intraparenchymal application of minimal amounts of trophic factors might be therapeutically desirable. We compared the effectiveness of intrastriatal and intracerebroventricular administrations of NGF on striatal cholinergic neurons in adult rats. Daily intrastriatal administration for 1 week of > or = 50 ng of NGF resulted in an increase in mRNA levels for choline acetyltransferase (ChAT) in striatal cholinergic cells to approximately 2-fold over control. A daily intraventricular dose of 4.5 micrograms of NGF was required for a similar response. Both 5 and 50 ng of NGF/day failed to induce an effect on transmembrane protein tyrosine kinase trkA mRNA levels, but injections of 750 or 1500 ng/day of NGF up-regulated trkA mRNA expression to approximately 2-fold of control. NGF delivered intracerebroventricularly failed to induce an observable change in striatal trkA mRNA, even at a dosage of 4.5 micrograms of NGF/day. These quantitative differences in NGF actions were reflected at the level of NGF receptors. Using Western blotting procedures, we found pronounced tyrosine phosphorylation of Trk-type proteins 2 hr after intrastriatal injection of 50 ng of NGF. Maximal responses were seen with either 150 or 750 ng of NGF. For maximal activation of Trks by intraventricular NGF injection, 4.5 micrograms of NGF was required. Taken together, our results strongly favor intraparenchymal injections or infusions of NGF, and possibly other trophic factors, for therapeutical applications to maximize the effects on the targeted neuronal populations and to minimize undesirable side effects.
Mol Pharmacol 1996 Feb
PMID:Trophic effect of exogenous nerve growth factor on rat striatal cholinergic neurons: comparison between intraparenchymal and intraventricular administration. 863 63

It is well established that leucine-rich repeat (LRR) proteins such as connectin, slit, chaoptin, and Toll have pivotal roles in neuronal development in Drosophila as cell adhesion molecules. However, to date, little information concerning mammalian LRR proteins has been reported. In the present study, we sought LRR proteins of the mouse brain, based on the assumption that fundamental mechanisms are conserved between different species. We screened a neonatal mouse brain cDNA library with a human partial cDNA encoding LRR protein as a probe. We obtained two independent cDNAs encoding LRR proteins, designated NLRR-1 and NLRR-2 (Neuronal Leucine-Rich Repeat proteins). We analyzed the whole sequence of NLRR-1 and partial sequence of NLRR-2. Sequence analysis showed that these two clones are about 60% homologous to each other, and that NLRR-1 protein is a transmembrane protein. Northern blot analysis and in situ hybridization histochemistry showed that both NLRR-1 and NLRR-2 mRNAs were expressed primarily in the central nervous system (CNS); NLRR-1 mRNA was also detected in the non-neuronal tissues such as cartilage, while NLRR-2 mRNA expression was confined to the CNS at all developmental stages. These results suggest that there is at least one LRR protein family in the mouse and that these molecules may play significant but distinct roles in neural development and in the adult nervous system.
Brain Res Mol Brain Res 1996 Jan
PMID:Molecular cloning of novel leucine-rich repeat proteins and their expression in the developing mouse nervous system. 871 37

Activin is a protein growth and differentiation factor that initiates intracellular events through the activation of a complex of transmembrane protein serine kinases. Two subfamilies of receptor serine kinases, type I and type II, have been identified, and both receptor types may be required to generate a transmembrane signal. Investigation of the interaction between various activin receptors (ActRs) revealed that ActRs I and II could exist in a stable complex and that formation of that complex between transiently overexpressed molecules was not regulated by ligand. Analysis of phosphorylation suggested that activin induced phosphorylation of receptor I, probably at residues within a conserved glycine and serine-rich sequence in the juxtamembrane region referred to as the GS domain. Phosphorylation of the GS domain was dependent upon a functional ActRII. Introduction of an activin type I receptor, ALK4, into the mink lung epithelial cell line, L17, conferred activin responsiveness on those cells. Mutation of specific combinations of serines and threonines in the core sequence of the ALK4 GS domain to alanine rendered that receptor incompetent for signaling. Mutation of the same sets of residues to glutamic acid produced molecules that supported activin signaling but that did not display elevated basal signaling anticipated for a constitutively active receptor. However, mutation of a threonine residue in the carboxy-terminal half of the GS domain, T206, to glutamic acid yielded receptors with constitutive activity. Taken together, these results support a role for phosphorylation of type I ActRs in the generation of a biological signal.
Mol Endocrinol 1996 Apr
PMID:Formation and activation by phosphorylation of activin receptor complexes. 872 82

Myxococcus xanthus contains a large family of genes encoding eukaryotic-like serine/threonine kinases. Among them, two genes, pkn5 and pkn6, are divergently located on the chromosome and share a 46 bp promoter region between their transcription initiation sites, as determined by RNA protection. Pkn5, consisting of 380 amino acid residues, is a soluble protein in the cytoplasm, while Pkn6, consisting of 710 amino acid residues, is a transmembrane protein. Its membrane topology was determined using the Pkn6-PhoA fusion protein in Escherichia coli, which has a single transmembrane domain with the N-terminal domain in the cytoplasm and the C-terminal domain outside the cytoplasmic membrane. Both proteins, when expressed in E. coli, were autophosphorylated: Pkn5 only at Ser, and Pkn6 at both Ser and Thr. In M. xanthus, both genes are expressed constitutively throughout the life cycle, with slight increases at an early stage of development. Most strikingly, a pkn5-deletion strain forms fruiting bodies much faster than the wild-type strain, while a pkn6-deletion strain develops slower than the wild-type strain. These results, together with the fact that the pkn5-deletion strain is able to form fruiting bodies on semi-rich media, suggest that Pkn5 and Pkn6 have reciprocal roles in M. xanthus growth and development. Furthermore, Pkn6 may be a transmembrane sensor of external signals for development, while Pkn5 is a kinase that negatively regulates M. xanthus development.
Mol Microbiol 1996 Apr
PMID:Reciprocal regulation of the differentiation of Myxococcus xanthus by Pkn5 and Pkn6, eukaryotic-like Ser/Thr protein kinases. 873 41

Protein tyrosine phosphorylation and dephosphorylation are important in cell proliferation, differentiation and functioning of the central nervous system. We have identified a cDNA clone encoding a new transmembrane protein tyrosine phosphatase from a chicken brain cDNA library. The predicted amino acid sequence contains two phosphatase tandem repeats in the intracellular domain and multiple glycosylation sites in the extracellular domain. Since its intracellular domain shares 94% identity with human PTP alpha, we call it chicken PTP alpha (ChPTP alpha). Antibodies specific to ChPTP alpha recognize two major protein bands at 130 and 85 kDa in immunoblot and immunoprecipitation. ChPTP alpha transcript and protein are found in many tissues, but they are particularly abundant in brain. To gain insight into the function of PTP alpha s, we investigated the cell-type specific localization of ChPTP alpha in cerebellum by in situ hybridization and immunostaining. Throughout development, the level of ChPTP alpha remains similar from embryonic day 7 to post-hatching day 14, but the abundance and distribution of cells expressing this protein vary systematically through this period. During development, ChPTP alpha appears in pre-migratory and migrating granule cells, and in Bergmann glia and their radial processes. By 2-weeks after hatching, ChPTP alpha disappears from all cells of the cerebellum except Bergmann glia. Our data, which show for the first time the temporal and spacial distribution of a PTP alpha, suggest that these transmembrane phosphatases are important in the differentiation and function of Bergmann glia and in the migration of granule cells, and thereby play a role in development of the cerebellum.
Brain Res Mol Brain Res 1996 Apr
PMID:Characterization of chicken protein tyrosine phosphatase alpha and its expression in the central nervous system. 873 30

While constructing a catalog of mouse cDNAs which are expressed in the maternal-fetal interface during the peri-implantation period, we encountered a 1.6 kb cDNA clone showing a strong sequence similarity to the 3' untranslated region of the human dystroglycan gene. We cloned an additional 1.7 kb cDNA by reverse transcriptase-PCR (RT-PCR) and confirmed that this is a true mouse homolog of human dystroglycan cDNA by sequence analyses, Southern blotting, and genetic mapping of this gene on the distal region of mouse chromosome 9. Although it is well established that dystroglycan, a transmembrane protein, plays an important role in muscle tissues by bridging intracellular dystrophin to the laminin in the extracellular matrix, its role in non-muscle tissues remains elusive. To further investigate the role of the dystroglycan gene at the peri-implantation stage, we analyzed the expression patterns of this gene by in situ hybridization, which revealed that this gene is specifically expressed in decidual cells, especially in the cells surrounding the implantation site at 6.5, 7.5, and 8.5 day post conception (p.c.) stages, but not expressed in non-pregnant endometrial cells of uterus nor in the decidua at 12.5 day p.c. Further analyses by RT-PCR confirmed that the amount of dystroglycan mRNA in 8.5 day p.c. decidua was indeed 100-fold higher than that of non-pregnant uterus and 12.5 day p.c. mature placenta. These results suggest that dystroglycan may work as a mediator for adhesion between decidual cells themselves or between decidual cells and trophoblast cells, and provide a structural and functional support for maintaining pregnancy at its early stage.
Hum Mol Genet 1996 Sep
PMID:Cloning and expression analyses of mouse dystroglycan gene: specific expression in maternal decidua at the peri-implantation stage. 887 65

The periplasmic Escherichia coli enzyme DsbA catalyses the efficient formation of disulphide linkages in numerous extracytoplasmic proteins. Enteropathogenic E. coli, a major cause of infantile diarrhoea worldwide, expresses a type IV fimbria known as the bundle-forming pilus that promotes adherence to tissue-culture cells. In this study, we report that transposon insertions in the dsbA locus abolish adherence and dramatically reduce the level of bundlin, the major structural subunit of the pilus encoded by the bfpA locus. Adherence and bundlin levels are restored by complementation with the cloned dsbA gene. DsbA has no effect on bfpA transcription as measured with bfpA-lacZ fusions. Replacement of either cysteine codon 129 or 179 of bfpA with a serine codon results in reduced levels of bundlin, similar to the effect of the dsbA mutation. As is the case with dsbA mutants, this decreased level of bundlin is not due to decreased transcription. The half-life of bundlin as detected by pulse-chase experiments is dramatically reduced in a dsbA mutant in comparison to the wild type. The effect of DsbA on bundlin oxidation is independent of signal-peptide processing. Thus, we demonstrate that the DsbA enzyme is critical for the biogenesis of a type IV fimbria because of the essential role of a disulphide bond in the stability of the major structural subunit. These data illuminate the early steps in the biogenesis of type IV fimbriae by demonstrating that newly synthesized prepilin is a transmembrane protein accessible to periplasmic and cytoplasmic processing enzymes.
Mol Microbiol 1996 Aug
PMID:DsbA is required for stability of the type IV pilin of enteropathogenic escherichia coli. 887 41


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