scholarly journals Evolvable signaling networks of receptor tyrosine kinases: relevance of robustness to malignancy and to cancer therapy

2007 ◽  
Vol 3 (1) ◽  
pp. 151 ◽  
Author(s):  
Ido Amit ◽  
Ron Wides ◽  
Yosef Yarden
Keyword(s):  
Cancer Therapy ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Signaling Networks

scholarly journals Receptor Tyrosine Kinases Fall into Distinct Classes Based on Their Inferred Signaling Networks

2013 ◽  
Vol 6 (284) ◽  
pp. ra58-ra58 ◽  
Author(s):  
J. P. Wagner ◽  
A. Wolf-Yadlin ◽  
M. Sevecka ◽  
J. K. Grenier ◽  
D. E. Root ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Signaling Networks

scholarly journals Receptor Tyrosine Kinases as Target for Anti-Cancer Therapy

2002 ◽  
Vol 8 (22) ◽  
pp. 1959-1972 ◽  
Author(s):  
S. Brunelleschi ◽  
L. Penengo ◽  
M. Santoro ◽  
G. Gaudino
Keyword(s):  
Cancer Therapy ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Anti Cancer

The discovery of receptor tyrosine kinases: targets for cancer therapy

2004 ◽  
Vol 4 (5) ◽  
pp. 361-370 ◽  
Author(s):  
Andreas Gschwind ◽  
Oliver M. Fischer ◽  
Axel Ullrich
Keyword(s):  
Cancer Therapy ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases

scholarly journals Spatial and temporal alterations in protein structure by EGF regulate cryptic cysteine oxidation

2019 ◽  
Author(s):  
Jessica B Behring ◽  
Sjoerd van der Post ◽  
Arshag D Mooradian ◽  
Matthew J Egan ◽  
Maxwell I Zimmerman ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Redox Regulation ◽  
Receptor Tyrosine Kinases ◽  
Redox Signaling ◽  
Signaling Networks ◽  
Cysteine Oxidation ◽  
Time Resolved ◽  
Cellular Redox ◽  
Redox Biology ◽  
Stimulation Of

AbstractStimulation of receptor tyrosine kinases (RTK) such as EGF locally increase reactive oxygen species (ROS) levels at the plasma membrane that oxidize cysteines in proteins to enhance downstream signaling. Spatial confinement of ROS is an important regulatory mechanism to redox signaling, but it remains unknown why stimulation of different receptor tyrosine kinases (RTKs) at the plasma membrane target distinct sets of downstream proteins. To uncover additional mechanisms specifying which cysteines are redox regulated by EGF stimulation, we performed time-resolved quantification of the oxidation of 4,200 cysteine sites subsequent to EGF stimulation in A431 cells. EGF induces three distinct spatiotemporal patterns of cysteine oxidation in functionally organized protein networks, consistent with the spatial confinement model. Unexpectedly, protein crystal structure analysis and molecular dynamic simulation indicate widespread redox regulation of cryptic cysteines that are only solvent exposed upon changes in protein conformation. Phosphorylation and increased flux of nucleotide substrates serve as two distinct modes by which EGF specifies which cryptic cysteines become solvent exposed and redox regulated. Since proteins structurally regulated by different RTKs or cellular perturbations are largely unique, solvent exposure and redox regulation of cryptic cysteines is an important mechanism contextually delineating redox signaling networks.Significance StatementCellular redox processes are interconnected, but are not in equilibrium. Thus, understanding the redox biology of cells requires a systems-level, rather than reductionist, approach. Factors specifying which cysteines are redox regulated by a stimulus remain poorly characterized but are critical to understanding the fundamental properties of redox signaling networks. Here, we show that EGF stimulation induces oxidation of specific cysteines in 3 distinct spatiotemporal patterns. Redox regulated proteins include many proteins in the EGF pathway as well as many cysteines with known functional importance. Many redox regulated cysteines are cryptic and solvent exposed by changes in protein structure that were induced by EGF treatment. The novel finding that cryptic cysteines are redox regulated has important implications for how redox signaling networks are specified and regulated to minimize crosstalk. In addition, this time-resolved dataset of the redox kinetics of 4,200 cysteine sites is an important resource for others and is an important technological achievement towards systems-level understanding of cellular redox biology.

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