The torso pathway in Drosophila: a model system to study receptor tyrosine kinase signal transduction

Development ◽  
1993 ◽  
Vol 119 (Supplement) ◽  
pp. 47-56 ◽  
Author(s):  
Xiangyi Lu ◽  
Lizabeth A. Perkins ◽  
Norbert Perrimon
Keyword(s):  
Signal Transduction ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Current Knowledge ◽  
Current Model ◽  
Drosophila Embryo ◽  
Receptor Protein ◽  
Future Research ◽  
Threonine Kinase ◽  
Gap Genes

In the Drosophila embryo, specification of terminal cell fates that result in the formation of both the head (acron) and tail (telson) regions is under the control of the torso (tor) receptor tyrosine kinase. The current knowledge suggests that activation of tor at the egg pole initiates a signal transduction pathway that is mediated sequentially by the guanine nucleotide releasing factor son of sevenless (Sos), the p21Ras1 GTPase, the serine/threonine kinase D-raf and the tyrosine/threonine kinase MAPKK (Dsor1). Subsequently, it is postulated that activation, possibly by phosphorylation, of a transcription factor at the egg poles activates the transcription of the terminal gap genes tailless and huckebein. These gap genes, which encode putative transcription factors, then control the expression of more downstream factors that ultimately result in head and tail differentiation. Also involved in tor signaling is the non-receptor protein tyrosine phosphatase corkscrew (csw). Here, we review the current model and discuss future research directions in this field.

Torso signalling regulates terminal patterning in Drosophila by antagonising Groucho-mediated repression

Development ◽  
1997 ◽  
Vol 124 (19) ◽  
pp. 3827-3834 ◽  
Author(s):  
Z. Paroush ◽  
S.M. Wainwright ◽  
D. Ish-Horowicz
Keyword(s):  
Gene Expression ◽  
Dna Binding ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Drosophila Embryo ◽  
Gap Gene ◽  
Gap Genes ◽  
Developmental Contexts

Patterning of the non-segmental termini of the Drosophila embryo depends on signalling via the Torso receptor tyrosine kinase (RTK). Activation of Torso at the poles of the embryo triggers restricted expression of the zygotic gap genes tailless (tll) and huckebein (hkb). In this paper, we show that the Groucho (Gro) corepressor acts in this process to confine terminal gap gene expression to the embryonic termini. Embryos lacking maternal gro activity display ectopic tll and hkb transcription; the former leads, in turn, to lack of abdominal expression of the Kruppel and knirps gap genes. We show that torso signalling permits terminal gap gene expression by antagonising Gro-mediated repression. Thus, the corepressor Gro is employed in diverse developmental contexts and, probably, by a variety of DNA-binding repressors.

Signaling in new directions

1995 ◽  
Vol 73 (3-4) ◽  
pp. 133-136 ◽  
Author(s):  
Haleh Vahidi Samiei
Keyword(s):  
Gene Expression ◽  
Signal Transduction ◽  
Tyrosine Kinase ◽  
Map Kinase ◽  
Receptor Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Molecular Level ◽  
Clear Cut ◽  
New Directions

Many laboratories, using a variety of organisms, have contributed to deciphering the identity and the order of the components leading from ligand-bound receptor tyrosine kinases to various intracellular events, including changes in gene expression. The gaps have only been filled recently. This minireview summarizes the findings and points out the degree of conservation of the same pathway in distant organisms, both at the molecular level and in terms of the consecutive steps. The review also looks at points at which this pathway might be diverging and points onto which other pathways might be converging. These interactions are not always clear cut, and understanding them will be the challenge for the future.Key words: signal transduction, receptor tyrosine kinase, RAS, RAF, MAP kinase.

scholarly journals FMS-like Tyrosine Kinase 3/FLT3: From Basic Science to Clinical Implications

2019 ◽  
Vol 99 (3) ◽  
pp. 1433-1466 ◽  
Author(s):  
Julhash U. Kazi ◽  
Lars Rönnstrand
Keyword(s):  
Signal Transduction ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Current Knowledge ◽  
Biological Effects ◽  
Acquired Resistance ◽  
Cell Proliferation And Differentiation ◽  
Functional Aspects ◽  
Proliferation And Differentiation ◽  
Targeted Inhibition

FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase that is expressed almost exclusively in the hematopoietic compartment. Its ligand, FLT3 ligand (FL), induces dimerization and activation of its intrinsic tyrosine kinase activity. Activation of FLT3 leads to its autophosphorylation and initiation of several signal transduction cascades. Signaling is initiated by the recruitment of signal transduction molecules to activated FLT3 through binding to specific phosphorylated tyrosine residues in the intracellular region of FLT3. Activation of FLT3 mediates cell survival, cell proliferation, and differentiation of hematopoietic progenitor cells. It acts in synergy with several other cytokines to promote its biological effects. Deregulated FLT3 activity has been implicated in several diseases, most prominently in acute myeloid leukemia where around one-third of patients carry an activating mutant of FLT3 which drives the disease and is correlated with poor prognosis. Overactivity of FLT3 has also been implicated in autoimmune diseases, such as rheumatoid arthritis. The observation that gain-of-function mutations of FLT3 can promote leukemogenesis has stimulated the development of inhibitors that target this receptor. Many of these are in clinical trials, and some have been approved for clinical use. However, problems with acquired resistance to these inhibitors are common and, furthermore, only a fraction of patients respond to these selective treatments. This review provides a summary of our current knowledge regarding structural and functional aspects of FLT3 signaling, both under normal and pathological conditions, and discusses challenges for the future regarding the use of targeted inhibition of these pathways for the treatment of patients.

scholarly journals Dual Role of the PTPN13 Tyrosine Phosphatase in Cancer

Biomolecules ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1659
Author(s):  
Soha Mcheik ◽  
Leticia Aptecar ◽  
Peter Coopman ◽  
Véronique D’Hondt ◽  
Gilles Freiss
Keyword(s):  
Current Knowledge ◽  
Biological Activities ◽  
Tyrosine Phosphatase ◽  
Tumor Formation ◽  
Receptor Protein ◽  
Cell Junction ◽  
Future Research ◽  
Tyrosine Kinase Signaling ◽  
Cancer Types ◽  
Oncogenic Protein

In this review article, we present the current knowledge on PTPN13, a class I non-receptor protein tyrosine phosphatase identified in 1994. We focus particularly on its role in cancer, where PTPN13 acts as an oncogenic protein and also a tumor suppressor. To try to understand these apparent contradictory functions, we discuss PTPN13 implication in the FAS and oncogenic tyrosine kinase signaling pathways and in the associated biological activities, as well as its post-transcriptional and epigenetic regulation. Then, we describe PTPN13 clinical significance as a prognostic marker in different cancer types and its impact on anti-cancer treatment sensitivity. Finally, we present future research axes following recent findings on its role in cell junction regulation that implicate PTPN13 in cell death and cell migration, two major hallmarks of tumor formation and progression.

Identification of Two Src Recruitment Sites in the Juxtamembrane Region of Flt3 with Opposing Effects on Flt3-Ligand-Induced Signaling.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2289-2289
Author(s):  
Lars Ronnstrand ◽  
Elke Heiss ◽  
Christina Sundberg ◽  
Kristina Masson ◽  
Malin Pedersen ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Src Family Kinases ◽  
Phosphorylation Sites ◽  
Flt3 Ligand ◽  
Erk Activation ◽  
Juxtamembrane Region ◽  
Signal Relay

Abstract Early signal relay steps upon ligand-binding to the receptor tyrosine kinase Flt3, i.e. sites of Flt3-autophosphorylation and subsequent docking partners, are mainly unresolved. Here we demonstrate for the first time identification of ligand-induced in vivo phosphorylation sites in Flt3. By immunoprecipitation of specific tryptic peptides contained in the juxtamembrane region of human Flt3 and subsequent radiosequencing we identified the tyrosine residues 572, 589, 591 and 599 as in vivo autophosphorylation sites. Focusing on Y589 and Y599, we examined Flt3-ligand-mediated responses in WT-Flt3, Y589F-Flt3 and Y599F-Flt3 expressing 32D cells. Compared to WT-Flt3-32D cells, 32D-Y589F-Flt3 showed upon ligand-stimulation enhanced Erk activation as well as proliferation/survival whereas 32D-Y599F-Flt3 cells displayed substantially diminished responses. Both pY589 and pY599 were identified as association sites for multiple signal relay molecules including Src family kinases. Consistently, 32D-Y589F-Flt3 and 32D-Y599F-Flt3 showed decreased FL-triggered Src activation, impaired phosphorylation of the adapter molecules Cbl and ShcA and deficient receptor ubiquitination and degradation. Interference with the Src-dependent negative regulation of Flt3 signaling may account for the enhanced mitogenic response of Y589F-Flt3. pY599 was additionally found to interact with the protein tyrosine phosphatase Shp2. As Y599F-Flt3-32D lacked ligand-induced Shp2 phosphorylation and since silencing of Shp2 in WT-Flt3-expressing cells mimicked the Y599F-Flt3-phenotype we hypothesize that recruitment of Shp2 to pY599 contributes to FL-mediated Erk activation and proliferation. To summarize, our work presents novel insights in Flt3-mediated signal transduction. We have identified the in vivo autophosphorylation sites of the juxtamembrane region of Flt3, revealed Src family kinases and Shp2 as binding partners of pY589 and/or pY599, respectively, as well as their potential impact on FL-mediated signaling in Flt3-32D cells. Future work will now focus on elucidation of additional and possibly novel interaction partners of the found phosphorylation sites by employing an unbiased proteomics approach. With this gained knowledge it will be of interest to see whether ITDs differing in the nature of the duplicated tyrosines also confer distinct signaling behavior. If so, these tyrosines might serve as a diagnostic marker and point towards a successful combinatorial therapy consisting of a receptor tyrosine kinase inhibitor and an inhibitor for the specifically affected signal transduction pathway.

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