Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Feb 1;167(2):151-163.
doi: 10.1093/jb/mvz085.

Redox regulation of tyrosine kinase signalling: more than meets the eye

Christopher M Dustin  1 , David E Heppner  2   3 , Miao-Chong J Lin  1 , Albert van der Vliet  1
Affiliations
Review

Redox regulation of tyrosine kinase signalling: more than meets the eye

Christopher M Dustin et al. J Biochem. .

Abstract

Protein kinases are essential mediators of cellular signal transduction and are often dysregulated in disease. Among these, protein tyrosine kinases (PTKs) have received specific interest due to their common roles in various diseases including cancer, and emerging observations indicating that PTK signalling pathways are susceptible to regulation by reactive oxygen species (ROS), which are also frequently implicated in disease pathology. While it is well recognized that ROS can impact on tyrosine kinase signalling by inhibiting tyrosine phosphatases, more recent studies highlight additional modes of redox-based regulation of tyrosine kinase signalling by direct redox modification of non-catalytic cysteines within tyrosine kinases or other protein components of this signalling pathway. In this review, we will present recent advancements with respect to redox-based mechanisms in regulating PTK signalling, with a specific focus on recent studies demonstrating direct redox regulation of Src-family kinases and epidermal growth factor receptor kinases. Importantly, redox-based modulation of tyrosine kinases may be relevant for many other kinases and has implications for current approaches to develop pharmacological inhibitors for these proteins.

Keywords: Redox; Src; EGFR; NOX; cysteine.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Basic components of tyrosine kinase signalling. Tyrosine kinase signalling involves the phosphorylation of a substrate protein via the addition of a phosphate to a substrate Tyr residue, catalysed by a kinase, leading to activation or inactivation of this target protein. Phosphorylated Tyr residues can act as a recognition site for SH2 domain-containing proteins that ‘read’ and transmit the signal. Protein tyrosine phosphorylation can be reversed through hydrolysis by a Tyr phosphatase.
Fig. 2
Fig. 2
Conservation of Cys residues in SFKs. Architecture of the c-Src kinase domain with regulatory αC-helix (red cartoon) and A-loop (orange cartoon) (PDB: 2SRC). Main chain spheres represent the composite locations of conserved cysteine residues across the kinome within the kinase domain (blue), the activation loop (orange) and within a conserved cysteine cluster distant from the ATP binding site (red).
Fig. 3
Fig. 3
(A) The nine Cys residues found in the c-Src kinase and their conservation within the SFKs. The Cys residues contained within the CXXXXXXXMXXCW domain conserved within Tyr kinases are indicated. (B) Crystal structure of c-Src (PDB: 2SRC) indicating the location of the nine Cys residues, as well as the regulatory Y416 and Y527 residues. CXXXXXXXMXXCW domain Cys residues are highlighted in red. Modified from (44).
Fig. 4
Fig. 4
Active asymmetric EGFR kinase dimer model showing the positions of the activator αH helix, containing the conserved CXXXXXXXMXXCW motif (cysteines of this motif shown as red spheres), and αC-helix (red) inward positioning in the active receiver kinase. αH and αC helix of the receiver and activator kinases, respectively, are labelled for clarity.
Fig. 5
Fig. 5
Diverse mechanisms of redox regulation of tyrosine kinase signalling. Cellular ROS (typically H2O2 but also including various RNS) can modify cysteines within PTPs, thereby inhibiting their activity and alleviating their inhibitory effects on PTK function or substrate phosphorylation (middle), leading to higher levels of activation. Alternatively, ROS can either positively or negatively regulate PTK function by cysteine oxidation (right), depending on the nature or site of cysteine modification. Additionally, ROS can modify cysteines in SH2 domain regions to impact on interaction with tyrosine phosphorylated proteins (left) or promote activation of some PTPs. The recognition of these domains can be influenced by PTP redox modification as SH2 domains require phospho-Tyr for target binding, but may also be influenced by redox on PTPs that have SH2 domains themselves. See manuscript text for further details.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Endicott J.A., Noble M.E., Johnson L.N. (2012) The structural basis for control of eukaryotic protein kinases. Annu. Rev. Biochem. 81, 587–613 - PubMed
    1. Pawson T., Gish G.D., Nash P. (2001) SH2 domains, interaction modules and cellular wiring. Trends Cell Biol. 11, 504–511 - PubMed
    1. Barford D., Das A.K., Egloff M.P. (1998) The structure and mechanism of protein phosphatases: insights into catalysis and regulation. Annu. Rev. Biophys. Biomol. Struct. 27, 133–164 - PubMed
    1. Zhang J., Yang P.L., Gray N.S. (2009) Targeting cancer with small molecule kinase inhibitors. Nat. Rev. Cancer 9, 28–39 - PubMed
    1. Holmstrom K.M., Finkel T. (2014) Cellular mechanisms and physiological consequences of redox-dependent signalling. Nat. Rev. Mol. Cell Biol. 15, 411–421 - PubMed

Substances