Our group is interested cellular responses to nitric
oxide (NO). NO has been found to signal through protein
thiol modification and perhaps through protein tyrosine
nitration. Such effects are likely to be critical
for NO-mediated induction of proteins such as heme
oxygenase -1 (HO-1), HSP70, g-glutamylcysteine synthetase,
cystine transporter (xCT) and modification of the
activity of a variety of proteins (eg caspase 3).
Each of these responses can be thought of as protective
and may contribute to NO's ability to provide protection
against oxidant injury and apoptosis. These activities
of NO may be especially important in maintaining vascular
homeostasis. The mechanisms by which NO regulates
protein expression are not clear.
However, since other oxidants have been found to
activate similar responses through activation of MAP
kinase pathways, mechanisms may be similar. In fact,
we have recently found that NO activates stress responsive
pathways leading to increased activity of ERK1/ERK2,
MAP kinase p38, and c-jun NH2-terminal kinases (JNKs).
Points at which NO initiates signaling are not known.
Among many possibilities, modification of G-proteins
(ras) or protein tyrosine phosphatases may be important.
Recent work in our lab has shown that protein tyrosine
phosphatase-1b (PTP-1b) is modified by NO leading
to PTP-1b inhibition and hyperphosphorylation of growth
factor receptors. Importantly, inhibition is rapidly
reversible by cellular redox systems so that NO-mediated
protein thiol oxidation and subsequent reduction represents
an 'on/off' mechanism for cell signaling.
