The sevenless signalling cassette mediates Drosophila EGF receptor function during epidermal development

Development ◽  
1994 ◽  
Vol 120 (3) ◽  
pp. 569-578 ◽  
Author(s):  
F.J. Diaz-Benjumea ◽  
E. Hafen
Keyword(s):  
Genetic Analysis ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Egf Receptor ◽  
Adaptor Protein ◽  
Receptor Function ◽  
Loss Of Function ◽  
Homozygous Mutant ◽  
Mutant Cells ◽  
Epidermal Development

In Drosophila, Drk, an SH2 adaptor protein, Sos, a putative activator of Ras1, Ras1, raf and rolled/MAP kinase have been shown to be required for signalling from the sevenless and the torso receptor tyrosine kinase. From these studies, it was unclear whether these components act in a single linear pathway as suggested by the genetic analysis or whether different components serve to integrate different signals. We have analyzed the effects of removing each of these components during the development of the adult epidermal structures by generating clones of homozygous mutant cells in a heterozygous background. Mutations in each of these signalling components produce a very similar set of phenotypes. These phenotypes resemble those caused by loss-of-function mutations in the Drosophila EGF receptor homolog (DER). It appears that these components form a signalling cassette, which mediates all aspects of DER signalling but that is not required for other signalling processes during epidermal development.

The torpedo (DER) receptor tyrosine kinase is required at multiple times during Drosophila embryogenesis

Development ◽  
1992 ◽  
Vol 115 (3) ◽  
pp. 853-872 ◽  
Author(s):  
R. Clifford ◽  
T. Schupbach
Keyword(s):  
Cell Death ◽  
Embryonic Development ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Egf Receptor ◽  
Temperature Shift ◽  
Loss Of Function ◽  
Primary Defect ◽  
Conditional Allele ◽  
Germband Retraction

The torpedo (DER) gene of Drosophila, which encodes a receptor tyrosine kinase of the EGF receptor subfamily, is essential for oogenesis, embryogenesis and imaginal disc development. To gain insight into the nature of the signals transduced by the torpedo product, we have characterized the gene's loss-of-function phenotype in the embryo. Through the induction of germline clones, we provide a genetic demonstration that maternal torpedo product does not contribute to zygotic development. Thus, the embryonic lethal phenotypes examined accurately reflect the consequences of eliminating all gene activity from the zygote. Temperature-shift experiments with the conditional allele topIF26 show that torpedo is required at two distinct times during embryonic development: the gene is first needed for germband retraction and for the production of anterior, posterior and ventral cuticle, then later for the secretion of ventral denticles. Since denticle formation can be severely disrupted in topIF26 animals without affecting cuticle production, the early and late requirements for torpedo appear to be functionally unrelated. torpedo, therefore, is required at multiple times in the development of the ventral epidermis, and may transduce qualitatively different signals. Since the early requirement for torpedo correlates with the first visible defect in embryonic development, increased cell death in the amnioserosa, cephalic ectoderm and ventral epidermis, the abnormalities in cuticle production and germband shortening seen in the mutant may be secondary consequences of a primary defect in cell viability. Given that the onset of cell death in torpedo embryos is not preceded by any obvious defects in mitogenesis, the establishment of cell identities or the maintenance of gene expression, it is possible that torpedo transduces a signal necessary for cell survival per se during early embryogenesis. During late embryogenesis, torpedo may mediate the reception of a second signal which regulates ventral epidermal cell differentiation.

scholarly journals Multiple functions of let-23, a Caenorhabditis elegans receptor tyrosine kinase gene required for vulval induction.

Genetics ◽  
1991 ◽  
Vol 128 (2) ◽  
pp. 251-267 ◽  
Author(s):  
R V Aroian ◽  
P W Sternberg
Keyword(s):  
Caenorhabditis Elegans ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Egf Receptor ◽  
Kinase Gene ◽  
Multiple Functions ◽  
Tyrosine Kinase Gene ◽  
Receptor Tyrosine Kinase Gene ◽  
Epidermal Growth ◽  
Mutant Phenotypes

Abstract The let-23 gene, which encodes a putative tyrosine kinase of the epidermal growth factor (EGF) receptor subfamily, has multiple functions during Caenorhabditis elegans development. We show that let-23 function is required for vulval precursor cells (VPCs) to respond to the signal that induces vulval differentiation: a complete loss of let-23 function results in no induction. However, some let-23 mutations that genetically reduce but do not eliminate let-23 function result in VPCs apparently hypersensitive to inductive signal: as many as five of six VPCs can adopt vulval fates, in contrast to the three that normally do. These results suggest that the let-23 receptor tyrosine kinase controls two opposing pathways, one that stimulates vulval differentiation and another that negatively regulates vulval differentiation. Furthermore, analysis of 16 new let-23 mutations indicates that the let-23 kinase functions in at least five tissues. Since various let-23 mutant phenotypes can be obtained independently, the let-23 gene is likely to have tissue-specific functions.

The receptor tyrosine kinase HIR-1 coordinates HIF-independent responses to hypoxia and extracellular matrix injury

2018 ◽  
Vol 11 (550) ◽  
pp. eaat0138
Author(s):  
Roman Vozdek ◽  
Yong Long ◽  
Dengke K. Ma
Keyword(s):  
Extracellular Matrix ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Large Scale ◽  
Hypoxia Inducible Factor ◽  
Metabolic Adaptation ◽  
Loss Of Function ◽  
Ecm Remodeling ◽  
C Elegans ◽  
Heme Peroxidases

Inadequate tissue oxygen, or hypoxia, is a central concept in the pathophysiology of ischemic disorders and cancer. Hypoxia promotes extracellular matrix (ECM) remodeling, cellular metabolic adaptation, and cancer cell metastasis. To discover new pathways through which cells respond to hypoxia, we performed a large-scale forward genetic screen inCaenorhabditis elegansand identified a previously uncharacterized receptor tyrosine kinase named HIR-1. Loss of function inhir-1phenocopied the impaired ECM integrity associated with hypoxia or deficiency in the oxygen-dependent dual oxidase, heme peroxidases, or cuticular collagens involved in ECM homeostasis. Genetic suppressor screens identified NHR-49 and MDT-15 as transcriptional regulators downstream of HIR-1. Furthermore,hir-1mutants showed defects in adapting to and recovering from prolonged severe hypoxia. We propose thatC. elegansHIR-1 coordinates hypoxia-inducible factor–independent responses to hypoxia and hypoxia-associated ECM remodeling through mechanisms that are likely conserved in other organisms.

scholarly journals Rapid uptake of tyrphostin into A431 human epidermoid cells is followed by delayed inhibition of epidermal growth factor (EGF)-stimulated EGF receptor tyrosine kinase activity.

1991 ◽  
Vol 11 (5) ◽  
pp. 2697-2703 ◽  
Author(s):  
C A Faaland ◽  
F H Mermelstein ◽  
J Hayashi ◽  
J D Laskin
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Kinase Activity ◽  
Egf Receptor ◽  
Tyrosine Kinase Activity ◽  
A431 Cells ◽  
Epidermal Growth

Treatment of A431 human epidermoid cells with epidermal growth factor (EGF; 20 nM) results in decreased proliferation. This is associated with blockage of the cells in the S and/or G2 phases of the cell cycle. We found that tyrphostin, a putative tyrosine kinase inhibitor, in the range of 50 to 100 microM, partially reversed the growth-inhibitory and cell cycle changes induced by EGF. By using high-pressure liquid chromatography with electrochemical detection, we found that tyrphostin was readily incorporated into A431 cells, reaching maximal levels within 1 h. Although tyrphostin (50 to 100 microM) had no effect on high-affinity binding of EGF to its receptor in A431 cells for up to 24 h, the compound partially inhibited EGF-stimulated EGF receptor tyrosine kinase activity. However, this effect was evident only after prolonged treatment of the cells (4 to 24 h) with the drug. When the peak intracellular concentration of tyrphostin occurred (1 h), no inhibition of tyrosine kinase activity was observed. After both 1 and 24 h, tyrphostin was a less effective inhibitor of tyrosine kinase activity than the potent tumor promoter 12-O-tetradecanoyl phorbol-13-acetate, which almost completely blocked EGF receptor autophosphorylation. On the basis of our data, we hypothesize that tyrphostin is not a competitive inhibitor of the EGF receptor tyrosine kinase in intact cells and that it functions by an indirect mechanism.

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