FOR IMMEDIATE RELEASE
January 5, 1998
WITH A MOLECULAR SWISH OF THE HIPS,
GROWTH FACTOR INHIBITS KEY REGULATOR
OF IMMUNE SYSTEM'S T-CELL RESPONSE
UCSF researchers report that they have made a novel--and
surprising--finding that could offer new insights into the way in which
immune system T-cells are regulated.
In the Jan. 2 issue of Science, they report that an extracellular
signal prevented a key enzyme-like receptor from carrying out its
regulatory role on T-cells. The receptor, CD45, is a protein tyrosine
phosphatase required for initiating the response of T-cells to perceived
pathogens.
While T-cells are critical for mounting immunological responses to
pathogens, they also are involved in allograft rejection and autoimmune
diseases. Thus, understanding CD45 regulation could shed light on T-cell
responses, which, in turn, could ultimately lead to improved treatments for
immune disorders.
In an even more unexpected finding, the scientists also report that
inhibition of the CD45 phosphatase receptor is caused by dimerization, a
process in which two adjacent molecules in the receptor's extracellular
domain wedge together, in a molecular swish of the hips.
This is particularly significant, because dimerization of the
extracellular domain in enzyme-like receptors had previously been known
only to catalyze reactions--each molecular tail sparking action in the
other. The formation of the dimer, or molecular subunits, in the CD45
phosphatase receptor apparently caused each molecule to block the other's
catalytic site.
"This is a novel finding," says Arthur Weiss, MD, PhD, a professor
of medicine at the University of California San Francisco, a Howard Hughes
Medical Institute investigator and the principal investigator of the study.
"Dimerization of almost every other type of receptor has always been viewed
as activating. This observation provides evidence that dimerization of a
receptor inhibits its function and provides molecular evidence for how that
occurs. It is also the first clue regarding the regulation of this class
of transmembrane enzymes."
Because the molecular factor, or ligand, that naturally binds to
the CD45 phosphatase receptor's extracellular domain is not known, the
scientists created a model receptor to probe CD45 regulation. The model
was a chimera of the epidermal growth factor receptor and CD45. As growth
factor is a common regulatory factor in T-cells, the UCSF finding suggests
the likelihood that some factor has the ability to inhibit CD45 phosphatase
activity.
While little is known about the way in which the protein tyrosine
phosphatase receptor functions and is regulated, scientists do know that it
acts in concert with another intracellular enzyme, Lck, a tyrosine kinase.
The two enzymes control the cascade of signaling molecules that drive
T-cells to become activated--alerting the cells to danger, prompting a
response and then getting them to settle down again.
Tyrosine kinases initiate the signaling cascade, through the
process of phosphorylation, in which a phosphate group is added to a
signaling protein, stimulating action. The CD45 tyrosine phosphatase, in
turn, removes a phosphatate group, inhibiting Lck kinase function and
thereby stopping the T-cell response. Thus, the two receptors play
complementary roles in controlling T-cell response.
The researchers focused specifically on the CD45 tyrosine
phosphatase receptor because it is the major transmembrane phosphatase
receptor expressed on T-cells and has been strongly implicated in T-cell
development and function. In the absence of this receptor, there is
developmental arrest in mice. Research also indicates that at least two
people have been immunodeficient as a result of the absence of this
receptor in T-cells.
So little is known about how tyrosine phosphatase receptors
function that it is not even clear that they are regulated at their
extracellular domain--nor what that domain looks like. The UCSF
researchers added the epidermal growth factor extracellular domain to try
and tease out some answers to these questions.
Now, says Weiss, the researchers need to find out what the
naturally occurring extracellular domain looks like--and what molecule
binds to it. And they need to determine how important their observation
regarding dimerization is.
To this end, they plan to insert a mutation that inactivates the
observed inhibitory dimer wedge into the CD45 gene in a mouse. Presumably,
says Weiss, the mutation will inactivate the inhibitory wedge, allowing the
enzyme-like receptor to carry out the process of dephosphorylation in an
unregulated fashion.
"This may also give us clues about what the ligand [molecule at the
binding site] is because we'll see where, when and how the immune response
is perturbed and it may help us do a ligand search."
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