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 kinasesenzymes 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 TAB1a "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.