The Road Less Traveled: TSRI Scientists Find Alternative
Path for Activation of Crucial Enzyme
A group of scientists at The Scripps Research Institute
(TSRI) have demonstrated the unexpected ability of an important
human enzyme to activate itself, when previously the activation
of the enzyme was believed to depend on the action of other
enzymes.
Scientists had thought that the enzyme, called p38a, relied
upon other human enzymes to activate it, and that its activation
pathway was well studied and characterized. The discovery
that the enzyme can activate itself, published last month
in the journal Science, has important implications
for drugs that target p38a.
"[Everyone] always thought MAP [mitogen-activated protein]
kinases went through this classical cascade with several different
kinases," says Department of Immunology Associate Professor
Jiahuai Han, who led the study. "This is the first time we
are seeing an alternative activation pathway."
"It provides a whole new paradigm for understanding MAP
kinase activation," says Richard Ulevitch, professor and chair
of the Department of Immunology at TSRI and one of the authors
of the report.
The enzyme p38a, which was first described by Han and Ulevitch
several years ago in Science, is one of many different
MAP kinases—enzymes crucial to every part of biology.
They are a class of signal transduction molecules that are
responsible for mediating cellular responses to external signals
in mammals.
Cells in higher organisms must respond to signals from other
cells in their surrounding tissue and from circulating cells
of the immune system in order to function properly. All the
normal activities in the life of a cell, from movement to
division to death, are initiated and controlled by such signaling.
Signaling MAP kinases are implicated in many diseases as
well, and inhibiting them may lead to treatments for diseases
as diverse as cancer and arthritis.
The widely held view of MAP kinase activation, including
p38a, is that activation occurs when a second enzyme attaches
a phosphate group to specific tyrosine and threonine residues
on the first enzyme's surface. This second enzyme must, itself,
be "phosphorylated" by a third enzyme, and the activation
of p38a is actually a cascade of reactions in which other
"upstream" enzymes first become activated and then activate
the p38a.
Previous to the current work, scientists believed that this
cascade was the only way that p38a could be activated.
But in the report, the group demonstrated that p38a has
the ability to autophosphorylate, activating itself, when
it is bound to a protein called TAB1—a "scaffolding"
protein that organizes large cellular assemblies.
The results have important implications for the design of
drugs that inhibit the p38a signaling cascade.
"People thought that if you could inhibit part of the cascade,
you would get the same result," says Han. "But you need to
consider [these results]. If you really want to inhibit the
p38 pathway in the most effective fashion, you need to target
p38."
The research article "MAPK-Independent Activation of p38a
Mediated by TAB1-Dependent Autophosphorylation of p38a" is
authored by Baoxue Ge, Hermann Gram, Franco Di Padova, Betty
Huang, Liguo New, Richard J. Ulevitch, Ying Luo, and Jiahuai
Han and appears in the February 15, 2002 issue of Science.
The research was funded by the National Institutes of Health.
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