The researchers determined that the SF-1 receptor is regulated by a cascade of signals initiated outside of the cell that, through a series of molecular events, ultimately cause a change in the molecular makeup of the receptor in the nucleus. This change, known as phosphorylation - the addition of a phosphate to the molecule - occurs in SF-1 at an activation region known as AF-1. And once it has, it prompts the receptor to recruit its co-activators, located at the traditional ligand-binding site, to help bring about changes in gene activity.
"It's been dogma that nuclear receptors are regulated by ligands," said the senior author of the study, Holly A. Ingraham, PhD, an associate professor of physiology and obstetrics, gynecology and reproductive sciences at UCSF. "Our work shows that phosphorylation of a single serine residue within an active domain (AF-1) of SF-1 modulates the activity of this nuclear receptor in the apparent absence of a ligand."
"The phosphorylation event somehow causes cross talk between the AF-1 domain being phosphorylated and the domain that interacts with the co-activators." (Similar results have been reported by Tremblay et al, in the same issue.)
The phosphorylation event itself appears to be initiated by a signaling pathway outside the cell known as map kinase.
The lead author of the study, Gary D. Hammer, MD, PhD, a research physiologist in the Departments of Physiology and Medicine at UCSF, was awarded the Endocrine Society 1999 Merck Senior Fellow award for this work last week.
The researchers conducted their investigation by trying to tease out the
suspected role of phosphorylation. They did so in part by phosphorylating two
versions of SF-1 - one mutated to be nonphosphorylatable, one a naturally
occurring form - and observing the ability of both to activate two SF-1 target
genes. One gene, MIS, is a growth factor that blocks
Contact: Jennifer O'Brien
University of California - San Francisco