An extended family of protein-tyrosine kinase genes differentially expressed in the vertebrate nervous system (original) (raw)
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Tissue-dependent regulation of protein tyrosine kinase activity during embryonic development
The Journal of Cell Biology, 1991
Protein tyrosine kinase activity was assayed in a variety of chicken tissues during embryonic development and in the adult. In some tissues protein tyrosine kinase activity decreased during embryonic development; however, in other tissues it remained high throughout development, it contrast to the level of protein tyrosine phosphorylation, which decreased during development. The highest levels of tyrosine kinase activity were detected in 17-d embryonic brain although only low levels of protein tyrosine phosphorylation were observed in this tissue. Several alternatives were examined in an effort to determine the mechanism responsible for the low levels of tyrosine phosphorylated proteins in most older embryonic and adult chicken tissues despite the presence of highly active tyrosine kinases. The results show that the regulation of protein tyrosine phosphorylation during embryonic development is complex and varies from tissue to tissue. Furthermore, the results suggest that protein tyrosine phosphatases play an important role in regulating the level of phosphotyrosine in proteins of many older embryonic and adult tissues.
Protein tyrosine phosphatase PTPRR isoforms : modulators of neuronal growth factor signalling
Cell Oncol, 2008
Community development and activity is critically dependent on communication between individuals. Likewise, proper growth and functioning of multicellular organisms requires communication between cells. In this process, extracellular stimuli that trigger the correct cellular responses through the activation of specific intracellular signalling pathways play a pivotal role. A key mechanism in cellular signal transduction is the reversible tyrosine phosphorylation of proteins, exerted by the concerted action of two classes of enzymes: protein tyrosine kinases (PTKs) that catalyse the addition of a phosphate group to a tyrosine residue, and protein tyrosine phosphatases (PTPs) that remove that phosphate group again. Although the number of genes in the human genome that encode PTPs roughly equals that of PTK-encoding genes, our knowledge on products of PTP genes is lagging behind that on PTK genes [1, 2]. Partly this can be explained by the fact that PTKs were discovered earlier than PTPs. In addition, immediately after their discovery, the role of PTKs was coupled to disease. Mutant forms of PTKs were found encoded by the genomes of tumour viruses and PTK signalling pathways appeared constitutively activated in malignant cells. In contrast, around the time of their first identification [3] PTPs were merely regarded as "housekeeping" proteins that served to terminate intracellular signalling initiated by PTKs. This view has changed considerably over the past decade. Nowadays, PTPs are known as downstream counteractors but also as upstream activators of PTKs. Furthermore, we now know that PTP activity is subjected to regulatory principles as well and, importantly, mutations in PTP genes are causative or directly involved in several developmental and acquired disorders, including several forms of cancer [4]. Thus, PTPs perform much more complex roles in intracellular signalling than initially anticipated. However, the physiological function(s) of most PTPs still remain(s) to be disclosed. This thesis provides an overview of our studies on PTPs that belong to the protein tyrosine phosphatase receptor-type R (PTPRR) isoform family. Using cell and animal models, information about the function of these proteins in • General introduction General introduction cellular signalling and control of locomotion was obtained. Before presenting this work, I will first introduce the reader to signalling mechanisms and components that are generally relevant for studies described in the upcoming chapters. Receptor tyrosine kinase signalling Many fundamental cellular processes like cell growth, differentiation, metabolism and survival are regulated by extracellular growth factors or cytokines. Since these factors are unable to pass the hydrophobic cell membrane, they exert their effects via binding to cell surface receptors. One such receptor family consists of the so-called receptor tyrosine kinases (RTKs) that have an intrinsic protein tyrosine kinase activity [5]. RTKs are single membrane spanning proteins consisting of an intracellular kinase domain and an extracellular ligand-binding domain that is usually glycosylated. This extracellular part often contains one or multiple copies of Ig-like, fibronectin type III-like, EGF-like or cysteine-rich domains [6]. In general, ligand binding to RTKs induces dimerisation of these receptors resulting in autophosphorylation of two different classes of tyrosine residues in their cytosolic domains. Autophosphorylation of tyrosine residues within the kinase domain increases the kinase activity and precedes phosphorylation of other tyrosine residues that are localized outside the kinase domain [7, 8]. These latter phosphotyrosines function as binding sites for SH2 (Src homology 2) or PTB (phosphotyrosine binding) domain-containing proteins. Binding provides a mechanism for the assembly and recruitment of downstream signalling complexes. Depending on the type of RTK that is activated, many different signalling pathways (e.g. the STAT, PLCγ, MAPK, PI3-K or Cdc42 cascade) can be switched on [5]. As an example of RTK signalling, the working mechanism of the TrkA signal transduction cascade will be described in detail.
Developmental control by the Drosophila EGF receptor homolog DER
Trends in Genetics, 1991
The DER protein has the canonical structure of a receptor tyrosine kinase belonging to the subclass that includes the vertebrate EGF receptor 1,2. While three members of this class have been identified in vertebrates, in Drosophila DER appears to be unique. The protein has a single transmembrane domain separating the intracellular and extracellular domains. The highest degree of sequence conservation is found in the intracellular kinase domain. The DER protein has also been shown to have tyrosine kinase activity, and can phosphorylate itself3. The carboxy-terminal region, beyond the kinase domain, contains the sites for autophosphorylation and shows the lowest degree of structural conservation, although this region plays a pivotal role in signal transduction (see below). The extracellular portion comprises four subdomains. Two are cysteinerich and are likely to generate the scaffold of the ligand-binding domain, but not its recognition specificity. The cysteine-rich subdomain closer to the membrane is the longer of the two. Interestingly, this structural feature is also found in the Caenorhabditis elegans EGF receptor homolog, encoded by the let-23 gene ~, but not in the vertebrate counterparts, indicating that the ancestral form of these receptors was probably similar to DER.
Molecular Brain Research, 1995
Growth factors and their receptors function in the nervous system to induce proliferation and differentiation of neuronal precursor cells and to support survival of mature neurons. We have isolated a murine growth factor receptor tyrosine kinase using an anti-phosphotyrosine antibody screening procedure and studied the pattern of expression. The deduced amino acid sequence of the kinase has all the characteristics of a growth factor receptor and consists of a putative extracellular domain, a transmembrane domain, and a tyrosine kinase domain. Sequence comparison with known receptor tyrosine kinases indicated that the murine kinase is a mouse homolog of tyro3, tyro3 belongs to the Axl/Ufo growth factor receptor family. In the putative extracellular domain, there are two Ig-like domains and two fibronectin type III repeats which are conserved in other members of the Axl/Ufo family receptors. Northern blot hybridization analysis showed that tyro3 is expressed at high levels in the brain of adult mice, although considerable expression was also observed in the testis. In situ hybridization analysis revealed that high levels of tyro3 are expressed in the cerebral cortex, the lateral septum, the hippocampus, the olfactory bulb, and in the cerebellum. The highest levels of tyro3 expression in the brain are associated with neurons. The preferential expression of tyro3 in specific regions of the adult mouse brain suggests that tyro3 may function as a novel neurotrophic factor receptor.
American Journal of Anatomy, 1995
Growth factors and their receptors play an important role in controlling cellular proliferation, migration, and differentiation during vertebrate embryogenesis. We have used the reverse transcription-polymerase chain reaction to survey the repertoire of receptor tyrosine kinases (TK) expressed during early embryogenesis of Xenopus laeuis. Twelve distinct Xenopus TK cDNA classes were identified among a total of 352 cDNAs screened. A single TK cDNA class has been described previously and encodes the fibroblast growth factor receptor FGFR-A1. The remaining 11 TK cDNA classes appear to encode novel genes of the FGFR, platelet-derived growth factor receptor (PDGFR), Eph, Csk, Tyk2, and Klg subfamilies. By RNase protection assays, Xenopus TK mRNAs are rare transcripts (<lo' mRNA molecules/embryo), and are usually found to be expressed also maternally in the embryo. Most Xenopus TK genes examined by whole-mount in situ hybridization were expressed widely in tissues derived from multiple germ layers. Two Eck-related genes, however, were found to be restricted in their expression to neural crest of the second (hyoid) arch. Our findings are consistent with the proposed function of TKs in the regulation of specification and differentiation of embryonic tissues.
Journal of Biological Chemistry, 1997
We report the identification and characterization of Dnrk (Drosophila neurospecific receptor kinase), a Drosophila gene encoding a putative receptor tyrosine kinase (RTK) highly related to the Trk and Ror families of RTKs. During Drosophila embryogenesis, the Dnrk gene is expressed specifically in the developing nervous system. The Dnrk protein possesses two conserved cysteine-containing domains and a kringle domain within its extracellular domain, resembling those observed in Ror family RTKs (Ror1, Ror2, and a Drosophila Ror, Dror). This protein contains the catalytic tyrosine kinase (TK) domain with two putative ATP-binding motifs, resembling those observed in another Drosophila RTK (Dtrk) that mediates homophilic cell adhesion. The TK domain of Dnrk, expressed in bacteria or mammalian cells, exhibits apparent autophosphorylation activities in vitro. The TK domain lacking the distal ATP-binding motif also exhibits autophosphorylation activity, yet to a lesser extent. In addition to its TK activity, there are several putative tyrosine-containing motifs that upon phosphorylation may interact with Src homology 2 regions of other signaling molecules. Collectively, these results suggest that Dnrk may play an important role in neural development during Drosophila embryogenesis.
Proceedings of The National Academy of Sciences, 1994
Tyrosine protein kinases are likely to play an important role in the maintenance and/or development of the nervous system. In this study we have used the PCR cloning technique to isolate sequences derived from tyrosine kinase genes expressed in cultured hippocampal neurons obtained from 17.5-day-old rat embryos. Nucleotide sequence analysis of 209 independent clones revealed sequences derived from 25 tyrosine kinases, of which two corresponded to previously unreported genes. One of the PCR clones, ptk-2, belongs to the Jak family of cytoplasmic tyrosine kinases. The second clone, ptk-3, was derived from a gene encoding an additional class of tyrosine kinase receptors whose extracellular domains contain regions of homology with coagulation factors V and VIII and complement component C1. Transcripts encoding the Ptk-3 receptor are present in a variety of embryonic and adult tissues with highest levels observed in brain. During development, ptk-3 transcripts are most abundant in the proliferative neuroepithelial cells of the ventricular zone, raising the possibility that this receptor may play an important role in the generation of the mammalian nervous system.
Journal of Neuroscience, 2013
Axonal branches of the trigeminal ganglion (TG) display characteristic growth and arborization patterns during development. Subsets of TG neurons express different receptors for growth factors, but these are unlikely to explain the unique patterns of axonal arborizations. Intrinsic modulators may restrict or enhance cellular responses to specific ligands and thereby contribute to the development of axon growth patterns. Protein tyrosine phosphatase receptor type O (PTPRO), which is required for Eph receptor-dependent retinotectal development in chick and for development of subsets of trunk sensory neurons in mouse, may be such an intrinsic modulator of TG neuron development. PTPRO is expressed mainly in TrkB-expressing (TrkB ϩ) and Ret ϩ mechanoreceptors within the TG during embryogenesis. In PTPRO mutant mice, subsets of TG neurons grow longer and more elaborate axonal branches. Cultured PTPRO Ϫ/Ϫ TG neurons display enhanced axonal outgrowth and branching in response to BDNF and GDNF compared with control neurons, indicating that PTPRO negatively controls the activity of BDNF/TrkB and GDNF/Ret signaling. Mouse PTPRO fails to regulate Eph signaling in retinocollicular development and in hindlimb motor axon guidance, suggesting that chick and mouse PTPRO have different substrate specificities. PTPRO has evolved to fine tune growth factor signaling in a cell-type-specific manner and to thereby increase the diversity of signaling output of a limited number of receptor tyrosine kinases to control the branch morphology of developing sensory neurons. The regulation of Eph receptor-mediated developmental processes by protein tyrosine phosphatases has diverged between chick and mouse.
Developmental Dynamics, 1995
Growth factors and their receptors play an important role in controlling cellular proliferation, migration, and differentiation during vertebrate embryogenesis. We have used the reverse transcription-polymerase chain reaction to survey the repertoire of receptor tyrosine kinases (TK) expressed during early embryogenesis of Xenopus laeuis. Twelve distinct Xenopus TK cDNA classes were identified among a total of 352 cDNAs screened. A single TK cDNA class has been described previously and encodes the fibroblast growth factor receptor FGFR-A1. The remaining 11 TK cDNA classes appear to encode novel genes of the FGFR, platelet-derived growth factor receptor (PDGFR), Eph, Csk, Tyk2, and Klg subfamilies. By RNase protection assays, Xenopus TK mRNAs are rare transcripts (<lo' mRNA molecules/embryo), and are usually found to be expressed also maternally in the embryo. Most Xenopus TK genes examined by whole-mount in situ hybridization were expressed widely in tissues derived from multiple germ layers. Two Eck-related genes, however, were found to be restricted in their expression to neural crest of the second (hyoid) arch. Our findings are consistent with the proposed function of TKs in the regulation of specification and differentiation of embryonic tissues.