Disease relevance of Tie

• When the tyrosine kinase homologous region was expressed in Escherichia coli, phosphorylation of proteins on tyrosine residues was observed with an antiphosphotyrosine antibody [1].
• The RET point mutations associated with MEN2A, MEN2B, or FMTC, or the chromosomal breakpoints and translocations associated with PTC, typically activate the RET receptor tyrosine kinase (RTK) [2].
• Dominant mutations in the Ret receptor tyrosine kinase lead to the familial cancer syndrome multiple endocrine neoplasia type 2 (MEN2) [3].
• BACKGROUND: The mammalian receptor protein tyrosine kinase (RTK), Anaplastic Lymphoma Kinase (ALK), was first described as the product of the t(2;5) chromosomal translocation found in non-Hodgkin's lymphoma [4].
• While the mechanism of ALK activation in non-Hodgkin's lymphoma has been examined, to date, no in vivo role for this orphan insulin receptor family RTK has been described [4].

High impact information on Tie

• Hrs regulates endosome membrane invagination and tyrosine kinase receptor signaling in Drosophila [5].
• CNK is required in multiple receptor tyrosine kinase pathways where it appears to be a tyrosine phosphorylation target [6].
• Our results suggest a model in which activation of the Sevenless receptor tyrosine kinase induces PHYL expression, which then acts with SINA to target the transcriptional repressor TTK88 for degradation, thereby promoting R7 cell fate specification [7].
• DOS is required not only for signal transduction via SEV but also in other receptor tyrosine kinase signaling pathways throughout development [8].
• The specification of the R7 photoreceptor cell in the developing eye of Drosophila is dependent upon activation of the Sevenless (SEV) receptor tyrosine kinase [8].

Biological context of Tie

• We wanted to investigate the relationship between receptor tyrosine kinase (RTK) activated signaling pathways and the induction of cell migration [9].
• We screened Drosophila melanogaster genomic and cDNA libraries by low-stringency hybridization with a probe representing the protein tyrosine kinase (TyK) domain encoded by a human alpha-platelet-derived growth factor receptor-encoding cDNA [10].
• R7 photoreceptor fate in the Drosophila eye induced by the activation of the Sevenless receptor tyrosine kinase and the RAS/MAP kinase signal transduction pathway [11].
• The Drosophila Abelson (abl) proto-oncogene homolog encodes a cytoplasmic tyrosine kinase that is expressed during embryogenesis primarily in developing CNS axons; abl mutants show no gross defects in CNS morphogenesis [12].
• The DNA sequence encodes a protein of 1520 amino acids with sequence homology to the human c-abl proto-oncogene product, beginning at the amino terminus and extending 656 amino acids through the region essential for tyrosine kinase activity [13].

Anatomical context of Tie

• Function of the Drosophila POU domain transcription factor drifter as an upstream regulator of breathless receptor tyrosine kinase expression in developing trachea [14].
• Control of photoreceptor cell fate by the sevenless protein requires a functional tyrosine kinase domain [15].
• In vertebrates, however, proximodistal patterning is regulated by receptor tyrosine kinase (RTK) activity from a source of ligands, fibroblast growth factors (FGFs), at the tip of the limb bud [16].
• We have isolated a RTK that is specifically expressed in electric organ and skeletal muscle [17].
• Because several other inductive events in development are mediated by receptor tyrosine kinases (RTKs), and because phosphotyrosine staining within muscle fibers is concentrated at synaptic sites, one possibility is that synapse-inducing signals are transduced by a RTK within the muscle fiber [17].

Associations of Tie with chemical compounds

• Ras1 and a putative guanine nucleotide exchange factor perform crucial steps in signaling by the sevenless protein tyrosine kinase [18].
• Class I phosphoinositide 3-kinases (PI(3)Ks) are activated through associated adaptor molecules in response to G protein-coupled and tyrosine kinase receptor signalling [19].
• The full-length sequence of Ltrk reveals most of the characteristics typical of Trk receptors, including highly conserved transmembrane and intracellular tyrosine kinase domains, and a typical extracellular domain of leucine-rich motifs flanked by cysteine clusters [20].
• At the poles of the Drosophila embryo, cell fate is established by a pathway that begins with the activation of a membrane-associated tyrosine kinase (the torso gene product); this then leads to activation of a serine/threonine kinase (Drosophila Raf-1) [21].
• Recently, the low molecular weight tyrosine kinase inhibitor ZD6474 was found to block the enzymatic activity of RET-derived oncoproteins in cultured cell lines [2].

Physical interactions of Tie

• The INR proreceptor (M(r) 280 kDa) is processed proteolytically to generate an insulin-binding alpha subunit (M(r) 120 kDa) and a beta subunit (M(r) 170 kDa) with protein tyrosine kinase domain [22].
• Son of sevenless binds to the SH3 domain of src-type tyrosine kinase [23].

Enzymatic interactions of Tie

• Torso contains a split tyrosine kinase domain and belongs to the type III subgroup of the RTK superfamily that also includes the platelet-derived growth factor receptors, stem cell or steel factor receptor c-Kit proto-oncoprotein, colony-stimulating factor-1 receptor, and vascular endothelial growth factor receptor [24].

Regulatory relationships of Tie

• We show that Elp mutations result from a single amino acid substitution in the kinase domain which activates tyrosine kinase activity and MAP kinase activation in tissue culture cells [25].
• The receptor tyrosine kinase pathways positively regulate Dfos and Djun [26].
• Receptor tyrosine kinase signaling regulates different modes of Groucho-dependent control of Dorsal [27].
• Here, we studied the structural requirements for Dos function in receptor tyrosine kinase mediated signaling processes by expressing mutated dos transgenes in the fly [28].
• Here we show that in Drosophila, the receptor tyrosine kinase Torso activates both STAT and Ras during the early phase of PGC development, and coactivation of STAT and Ras is required for PGC proliferation and invasive migration [29].

Other interactions of Tie

• This work provides the first genetic evidence that both Src42A and sag are modulators of RTK signaling [30].
• Sprouty is a general inhibitor of receptor tyrosine kinase signaling [31].
• Regulated Breathless receptor tyrosine kinase activity required to pattern cell migration and branching in the Drosophila tracheal system [32].
• Dof is needed in these cells for activation of the MAPK cascade via FGF signaling, but not for activation via other RTK ligands [33].
• In support of this hypothesis, we demonstrate that SHP-2, a vertebrate PTPase similar to Csw and previously implicated in RTK signaling, encodes the functional vertebrate homologue of Csw [34].

Analytical, diagnostic and therapeutic context of Tie

• Genetic dissection of signal transduction mediated by the sevenless receptor tyrosine kinase in Drosophila [35].
• Since p58/53 did not appear, by immunoblotting, to be related to any previously described tyrosine kinase substrate such as the SH2 containing proteins SHC and the tyrosine phosphatase Syp, the protein was purified in sufficient amounts to obtain peptide sequence [36].
• The strategy was developed further towards a generally applicable expression cloning system to identify signal transducers in tyrosine kinase pathways [37].
• Sampling the genomic pool of protein tyrosine kinase genes using the polymerase chain reaction with genomic DNA [38].
• The conductance, activated in response to endogenous signaling pathways in BIB-expressing oocytes, is decreased after treatment with 20 microm insulin and is enhanced with 10 microm lavendustin A, a tyrosine kinase inhibitor [39].

References