scholarly journals The PTB domain of ShcA couples receptor activation to the cytoskeletal regulator IQGAP1

2010 ◽  
Vol 29 (5) ◽  
pp. 884-896 ◽  
Author(s):  
Matthew J Smith ◽  
W Rod Hardy ◽  
Guang-Yao Li ◽  
Marilyn Goudreault ◽  
Steven Hersch ◽  
...  
Keyword(s):  
Receptor Activation ◽  
Ptb Domain

scholarly journals Evidence for a requirement for both phospholipid and phosphotyrosine binding via the Shc phosphotyrosine-binding domain in vivo.

1997 ◽  
Vol 17 (9) ◽  
pp. 5540-5549 ◽  
Author(s):  
K S Ravichandran ◽  
M M Zhou ◽  
J C Pratt ◽  
J E Harlan ◽  
S F Walk ◽  
...  
Keyword(s):  
Tyrosine Phosphorylation ◽  
Receptor Activation ◽  
Targeted Mutagenesis ◽  
Adapter Protein ◽  
Critical Component ◽  
Acidic Phospholipids ◽  
Phosphotyrosine Binding Domain ◽  
Ptb Domain

The adapter protein Shc is a critical component of mitogenic signaling pathways initiated by a number of receptors. Shc can directly bind to several tyrosine-phosphorylated receptors through its phosphotyrosine-binding (PTB) domain, and a role for the PTB domain in phosphotyrosine-mediated signaling has been well documented. The structure of the Shc PTB domain demonstrated a striking homology to the structures of pleckstrin homology domains, which suggested acidic phospholipids as a second ligand for the Shc PTB domain. Here we demonstrate that Shc binding via its PTB domain to acidic phospholipids is as critical as binding to phosphotyrosine for leading to Shc phosphorylation. Through structure-based, targeted mutagenesis of the Shc PTB domain, we first identified the residues within the PTB domain critical for phospholipid binding in vitro. In vivo, the PTB domain was essential for localization of Shc to the membrane, as mutant Shc proteins that failed to interact with phospholipids in vitro also failed to localize to the membrane. We also observed that PTB domain-dependent targeting to the membrane preceded the PTB domain's interaction with the tyrosine-phosphorylated receptor and that both events were essential for tyrosine phosphorylation of Shc following receptor activation. Thus, Shc, through its interaction with two different ligands, is able to accomplish both membrane localization and binding to the activated receptor via a single PTB domain.

scholarly journals FRS2 Proteins Recruit Intracellular Signaling Pathways by Binding to Diverse Targets on Fibroblast Growth Factor and Nerve Growth Factor Receptors

2000 ◽  
Vol 20 (3) ◽  
pp. 979-989 ◽  
Author(s):  
S. H. Ong ◽  
G. R. Guy ◽  
Y. R. Hadari ◽  
S. Laks ◽  
N. Gotoh ◽  
...  
Keyword(s):  
Nerve Growth Factor ◽  
Growth Factor ◽  
Binding Site ◽  
Fibroblast Growth Factor ◽  
Tyrosine Phosphorylation ◽  
Receptor Activation ◽  
Fibroblast Growth ◽  
Nerve Growth ◽  
Ptb Domain ◽  
Ptb Domains

ABSTRACT The docking protein FRS2 was implicated in the transmission of extracellular signals from the fibroblast growth factor (FGF) or nerve growth factor (NGF) receptors to the Ras/mitogen-activated protein kinase signaling cascade. The two members of the FRS2 family, FRS2α and FRS2β, are structurally very similar. Each is composed of an N-terminal myristylation signal, a phosphotyrosine-binding (PTB) domain, and a C-terminal tail containing multiple binding sites for the SH2 domains of the adapter protein Grb2 and the protein tyrosine phosphatase Shp2. Here we show that the PTB domains of both the α and β isoforms of FRS2 bind directly to the FGF or NGF receptors. The PTB domains of the FRS2 proteins bind to a highly conserved sequence in the juxtamembrane region of FGFR1. While FGFR1 interacts with FRS2 constitutively, independent of ligand stimulation and tyrosine phosphorylation, NGF receptor (TrkA) binding to FRS2 is strongly dependent on receptor activation. Complex formation with TrkA is dependent on phosphorylation of Y490, a canonical PTB domain binding site that also functions as a binding site for Shc (NPXpY). Using deletion and alanine scanning mutagenesis as well as peptide competition assays, we demonstrate that the PTB domains of the FRS2 proteins specifically recognize two different primary structures in two different receptors in a phosphorylation-dependent or -independent manner. In addition, NGF-induced tyrosine phosphorylation of FRS2α is diminished in cells that overexpress a kinase-inactive mutant of FGFR1. This experiment suggests that FGFR1 may regulate signaling via NGF receptors by sequestering a common key element which both receptors utilize for transmitting their signals. The multiple interactions mediated by FRS2 appear to play an important role in target selection and in defining the specificity of several families of receptor tyrosine kinases.

COVID-19 pathophysiology: interactions of gut microbiome, melatonin, vitamin D, stress, kynurenine and the alpha 7 nicotinic receptor: Treatment implications

2020 ◽  
Vol 3 (3) ◽  
pp. 322-345 ◽  
Author(s):  
George Anderson ◽  
Russel J Reiter
Keyword(s):  
Vitamin D ◽  
Coagulation Factors ◽  
Receptor Activation ◽  
Cytokine Induction ◽  
Aryl Hydrocarbon ◽  
Physiological Processes ◽  
Pulmonary Epithelial Cells ◽  
Vitamin D Levels ◽  
Complex Picture ◽  
Alpha 7

As data emerges on the pathophysiological underpinnings of severe acute respiratory syndrome coronavirus (SARS-CoV)-2, it is clear that there are considerable variations in its susceptibility and severity/fatality, which give indications as to its pathophysiology and treatment. SARS-CoV-2 modulatory factors include age, vitamin D levels, cigarette smoking, gender and ethnicity as well as premorbid medical conditions, including diabetes, cancer, obesity, cardiovascular disease, and immune-compromised conditions. A complex picture is emerging, with an array of systemic physiological processes interacting including circadian, immune, intestinal, CNS and coagulation factors. This article reviews data on SARS-CoV-2 pathoetiology and pathophysiology. It is proposed that a decrease in pineal and systemic melatonin is an important driver of SARS-CoV-2 susceptibility and severity, with the loss of pineal melatonin's induction of the alpha 7 nicotinic acetylcholine receptor (α7nAChR) in pulmonary epithelial cells and immune cells being a powerful regulator of susceptibility and severity, respectively. Stress, including discrimination stress, and decreased vitamin D also regulate SARS-CoV-2, including via gut dysbiosis and permeability, with a resultant decrease in the short-chain fatty acid, butyrate, and increase in circulating lipopolysaccharide. Stress and cytokine induction of the kynurenine pathways, leads to aryl hydrocarbon receptor activation, which primes platelets for heightened activity, coagulation and thrombin production, thereby driving elevations in thrombin that underpin many SARS-CoV-2 fatalities. On the basis of these pathophysiological changes, prophylactic and symptomatic treatments are proposed, including the use of melatonin and α7nAChR agonism. 

Effect of κ-opiate receptor activation on the levels of insulin, somatostatin and blood glucose in man

1989 ◽  
Vol 120 (3_Suppl) ◽  
pp. S230
Author(s):  
A. PFEIFFER ◽  
V. SCHUSDZIARRA ◽  
V. BRANTL
Keyword(s):  
Blood Glucose ◽  
Opiate Receptor ◽  
Receptor Activation

SHCA PHOSPHOTYROSINE DERIVED SIGNALING IS REQUIRED FOR THE MAINTENANCE OF CARDIAC FUNCTION

2008 ◽  
Vol 31 (4) ◽  
pp. 23
Author(s):  
Rachel Vanderlaan ◽  
Rod Hardy ◽  
Golam Kabir ◽  
Peter Back ◽  
A J Pawson
Keyword(s):  
Extracellular Matrix ◽  
Cardiac Function ◽  
Tyrosine Kinases ◽  
Sh2 Domain ◽  
Scaffolding Protein ◽  
Restricted Domain ◽  
Downstream Signaling ◽  
Matrix Interactions ◽  
Extracellular Matrix Interactions ◽  
Ptb Domain

Background: ShcA, a scaffolding protein, generates signalspecificity by docking to activated tyrosine kinases through distinct phosphotyrosine recognition motifs, while mediating signal complexity through formation of diverse downstream phosphotyrosine complexes. Mammalian ShcA encodes 3 isoforms having a modular architecture of a PTB domain and SH2 domain, separated by a CH1 region containing tyrosine phosphorylation sites important in Ras-MAPK activation. Objective and Methods: ShcA has a necessary role in cardiovascular development^1,2. However, the role of ShcA in the adult myocardium is largely unknown, also unclear, is how ShcA uses its signaling modules to mediate downstream signaling. To this end, cre/loxP technology was employed to generate a conditional ShcA allele series. The myocardial specific ShcA KO (ShcA CKO) and myocardial restricted domain mutant KI mice were generated using cre expressed from the mlc2v locus^3 coupled with the ShcA floxed allele and in combination with the individual ShcA domain mutant KI alleles^2. Results: ShcACKO mice develop a dilated cardiomyopathy phenotype by 3 months of life, typified by depressed cardiac function and enlarged chamber dimensions. Isolated cardiomyocytes from ShcA CKO mice have preserved contractility indicating an uncoupling between global heart function and single myocyte contractile mechanics. Force-length experiments suggest that the loss of shcAmediates the uncoupling through deregulation of extracellular matrix interactions. Subsequent, analysis of the ShcA myocardial restricted domain mutant KImice suggests that ShcA requires PTB domain docking to upstream tyrosine kinases and subsequent phosphorylation of the CH1 tyrosines important for downstream signaling. Conclusion: ShcA is required for proper maintenance of cardiac function, possibly regulation of extracellular matrix interactions. References: 1. Lai KV, Pawson AJ. The ShcA phosphotyrosine docking protein sensitizescardiovascular signaling in the mouse embryo. Genes and Dev 2000;14:1132-45. 2. Hardy WR. et al. Combinatorial ShcA docking interactions supportdiversity in tissue morphogenesis. Science2007;317:251-6. 3.Minamisawa, s. et al. A post-transcriptional compensatory pathway inheterozygous ventricular myosin light chain 2-deficient mice results in lack ofgene dosage effect during normal cardiac growth or hypertrophy. J Biol Chem 1999;274:10066-70.

Coaction of Electrostatic and Hydrophobic Interactions: Dynamic Constraints on Disordered TrkA Juxtamembrane Domain

2019 ◽  
Author(s):  
Zichen Wang ◽  
Huaxun Fan ◽  
Xiao Hu ◽  
John Khamo ◽  
Jiajie Diao ◽  
...  
Keyword(s):  
Single Molecule ◽  
Protein Function ◽  
Hydrophobic Interactions ◽  
Transmembrane Helix ◽  
Point Mutations ◽  
Salt Bridge ◽  
Receptor Activation ◽  
Membrane Dynamics ◽  
Juxtamembrane Domain ◽  
Joint Work

<p>The receptor tyrosine kinase family transmits signals into cell via a single transmembrane helix and a flexible juxtamembrane domain (JMD). Membrane dynamics makes it challenging to study the structural mechanism of receptor activation experimentally. In this study, we employ all-atom molecular dynamics with Highly Mobile Membrane-Mimetic to capture membrane interactions with the JMD of tropomyosin receptor kinase A (TrkA). We find that PIP<sub>2 </sub>lipids engage in lasting binding to multiple basic residues and compete with salt bridge within the peptide. We discover three residues insertion into the membrane, and perturb it through computationally designed point mutations. Single-molecule experiments indicate the contribution from hydrophobic insertion is comparable to electrostatic binding, and in-cell experiments show that enhanced TrkA-JMD insertion promotes receptor ubiquitination. Our joint work points to a scenario where basic and hydrophobic residues on disordered domains interact with lipid headgroups and tails, respectively, to restrain flexibility and potentially modulate protein function.</p>

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