scholarly journals Spatial Structure and pH-dependent Conformational Diversity of Dimeric Transmembrane Domain of the Receptor Tyrosine Kinase EphA1

2008 ◽  
Vol 283 (43) ◽  
pp. 29385-29395 ◽  
Author(s):  
Eduard V. Bocharov ◽  
Maxim L. Mayzel ◽  
Pavel E. Volynsky ◽  
Marina V. Goncharuk ◽  
Yaroslav S. Ermolyuk ◽  
...  
Keyword(s):  
Spatial Structure ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Transmembrane Domain ◽  
Conformational Diversity ◽  
Ph Dependent

Oligomerization of the extracellular domain of Boss enhances its binding to the Sevenless receptor and its antagonistic effect on R7 induction

1998 ◽  
Vol 111 (6) ◽  
pp. 737-747 ◽  
Author(s):  
E.A. Sevrioukov ◽  
J.H. Walenta ◽  
A. Sunio ◽  
M. Phistry ◽  
H. Kramer
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Compound Eye ◽  
Transmembrane Domain ◽  
Extracellular Domain ◽  
Antagonistic Effect ◽  
Lac Repressor ◽  
Receptor Complexes

In the developing compound eye of Drosophila, neuronal differentiation of the R7 photoreceptor cell is induced by the interaction of the receptor tyrosine kinase Sevenless with its ligand Bride of sevenless (Boss), which is expressed on the neighboring R8 cell. Boss is an unusual ligand of a receptor tyrosine kinase: it is composed of a large extracellular domain, a transmembrane domain with seven membrane-spanning segments and a cytoplasmic tail. Expression of a monomeric, secreted form of the extracellular domain of Boss is not sufficient for Sevenless activation, and instead acts as a weak antagonist. Because oligomerization appears to be a critical step in the activation of receptor tyrosine kinases, we used oligomerized forms of the Boss extracellular domain to test their ability to bind to Sevenless in vivo and restore R7 induction in vivo. Oligomerization was achieved by fusion to the leucine zipper of the yeast transcription factor GCN4 or to the tetramerization helix of Lac repressor. Binding of these multivalent proteins to Sevenless could be detected in vitro by immunoprecipitation of cross-linked ligand/receptor complexes and in vivo by receptor-dependent ligand localization. However, neither R8-specific or ubiquitous expression of multivalent Exboss ligands rescued the boss phenotype. Instead, these ligands acted as competitive inhibitors for wild-type Boss protein and thereby suppressed R7 induction. Therefore the role of the transmembrane or cytoplasmic domains of Boss in the activation of the Sev receptor cannot be replaced by oligomerization.

scholarly journals Modulation of Transmembrane Domain Interactions in Neu Receptor Tyrosine Kinase by Membrane Fluidity and Cholesterol

2019 ◽  
Vol 252 (4-5) ◽  
pp. 357-369 ◽  
Author(s):  
Muhammad Hasan ◽  
Dharmesh Patel ◽  
Natalie Ellis ◽  
Steven P. Brown ◽  
Józef R. Lewandowski ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Membrane Fluidity ◽  
Receptor Tyrosine Kinase ◽  
Transmembrane Domain ◽  
Domain Interactions

scholarly journals Dimerization of the EphA1 Receptor Tyrosine Kinase Transmembrane Domain: Insights into the Mechanism of Receptor Activation

Biochemistry ◽  
2014 ◽  
Vol 53 (42) ◽  
pp. 6641-6652 ◽  
Author(s):  
Matthieu Chavent ◽  
Alan P. Chetwynd ◽  
Phillip J. Stansfeld ◽  
Mark S. P. Sansom
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Transmembrane Domain ◽  
Receptor Activation

scholarly journals Transmembrane Domain Sequence Requirements for Activation of the p185c-neu Receptor Tyrosine Kinase

1997 ◽  
Vol 137 (3) ◽  
pp. 619-631 ◽  
Author(s):  
Lucinda I. Chen ◽  
Melanie K. Webster ◽  
April N. Meyer ◽  
Daniel J. Donoghue
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Tandem Repeats ◽  
Transmembrane Domain ◽  
Recent Observation ◽  
Growth Factor Receptor ◽  
Receptor Activation ◽  
Transmembrane Domains ◽  
Activating Mutations ◽  
Sequence Requirements

The receptor tyrosine kinase p185c-neu can be constitutively activated by the transmembrane domain mutation Val664→ Glu, found in the oncogenic mutant p185neu. This mutation is predicted to allow intermolecular hydrogen bonding and receptor dimerization. Understanding the activation of p185c-neu has assumed greater relevance with the recent observation that achondroplasia, the most common genetic form of human dwarfism, is caused by a similar transmembrane domain mutation that activates fibroblast growth factor receptor (FGFR) 3. We have isolated novel transforming derivatives of p185c-neu using a large pool of degenerate oligonucleotides encoding variants of the transmembrane domain. Several of the transforming isolates identified were unusual in that they lacked a Glu at residue 664, and others were unique in that they contained multiple Glu residues within the transmembrane domain. The Glu residues in the transforming isolates often exhibited a spacing of seven residues or occurred in positions likely to represent the helical interface. However, the distinction between the sequences of the transforming clones and the nontransforming clones did not suggest clear rules for predicting which specific sequences would result in receptor activation and transformation. To investigate these requirements further, entirely novel transmembrane sequences were constructed based on tandem repeats of simple heptad sequences. Activation was achieved by transmembrane sequences such as [VVVEVVA]n or [VVVEVVV]n, whereas activation was not achieved by a transmembrane domain consisting only of Val residues. In the context of these transmembrane domains, Glu or Gln were equally activating, while Lys, Ser, and Asp were not. Using transmembrane domains with two Glu residues, the spacing between these was systematically varied from two to eight residues, with only the heptad spacing resulting in receptor activation. These results are discussed in the context of activating mutations in the transmembrane domain of FGFR3 that are responsible for the human developmental syndromes achondroplasia and acanthosis nigricans with Crouzon Syndrome.

scholarly journals A novel pH-dependent membrane peptide that binds to EphA2 and inhibits cell migration

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Daiane S Alves ◽  
Justin M Westerfield ◽  
Xiaojun Shi ◽  
Vanessa P Nguyen ◽  
Katherine M Stefanski ◽  
...  
Keyword(s):  
Cell Migration ◽  
Receptor Tyrosine Kinase ◽  
Lipid Membranes ◽  
Transmembrane Domain ◽  
Activation Mechanism ◽  
Extracellular Medium ◽  
Akt Phosphorylation ◽  
Signaling Axis ◽  
Membrane Peptide ◽  
Ph Dependent

Misregulation of the signaling axis formed by the receptor tyrosine kinase (RTK) EphA2 and its ligand, ephrinA1, causes aberrant cell-cell contacts that contribute to metastasis. Solid tumors are characterized by an acidic extracellular medium. We intend to take advantage of this tumor feature to design new molecules that specifically target tumors. We created a novel pH-dependent transmembrane peptide, TYPE7, by altering the sequence of the transmembrane domain of EphA2. TYPE7 is highly soluble and interacts with the surface of lipid membranes at neutral pH, while acidity triggers transmembrane insertion. TYPE7 binds to endogenous EphA2 and reduces Akt phosphorylation and cell migration as effectively as ephrinA1. Interestingly, we found large differences in juxtamembrane tyrosine phosphorylation and the extent of EphA2 clustering when comparing TYPE7 with activation by ephrinA1. This work shows that it is possible to design new pH-triggered membrane peptides to activate RTK and gain insights on its activation mechanism.

Sign in / Sign up

Export Citation Format

Share Document