Redox-linked signal transduction pathways for protein tyrosine kinase activation.
The signaling for activation of protein tyrosine kinases (PTKs) is usually started by binding of ligands to cell-surface receptors. However, recent evidence suggests the presence of ligand binding-independent signaling pathways that are mediated by oxidative stress. Oxidation and reduction of protein cysteine sulfhydryl (SH) groups may work as a molecular switch to start or to stop the signaling. It is known that oxidation of cysteine SH groups on protein tyrosine phosphatases switches off the action of protein tyrosine phosphatases. This event may not, however, signal for initial autophosphorylation of previously unphosphorylated PTKs, whereas it certainly prevents dephosphorylation of once-phosphorylated PTKs. We have suggested new mechanisms for oxidative stress-mediated PTK activation. First, cell-surface glycosylphosphatidylinositol-anchoring proteins and a phosphoglycolipid/cholesterol-enriched membrane microdomain termed a "raft" can be the direct targets of oxidative stress for inducing their clustering through an S-S-bonded or S-X-S-bonded crosslinking of cell-surface proteins and subsequent activation of raft-associating Src family PTKs. Second, intracellular specific cysteine SH groups on PTK proteins can be another target of oxidative stress for inducing a conformational change necessary for initial activation of PTKs. A possible relationship between cell-surface and intracellular events is that the former frequently induces superoxide production as the second messenger for the latter.
Nakashima
Izumi
I
Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. inakashi@med.nagoya-u.ac.jp
Kato
Masashi
M
Akhand
Anwarul A
AA
Suzuki
Haruhiko
H
Takeda
Kozue
K
Hossain
Kahled
K
Kawamoto
Yoshiyuki
Y
D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D003545:Cysteine / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism; D008958:Models, Molecular; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism; D017382:Reactive Oxygen Species; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism; D026423:S-Nitroso-N-Acetylpenicillamine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D019061:src-Family Kinases
D017382:Reactive Oxygen Species; D011956:Receptors, Cell Surface; D026423:S-Nitroso-N-Acetylpenicillamine; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D017027:Protein Tyrosine Phosphatases; D003545:Cysteine