Regulatory Protein Modulates Transmembrane Signals

A regulatory protein called NHERF2 (sodium/hydrogen exchanger regulatory factor 2), a member of the PDZ class of proteins, has been shown to mediate the cell's response to binding of parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP). The study was reported in the June 20, 2002, issue of Nature.

PDZ domains were first identified as regions of sequence homology found in diverse signaling proteins. The name PDZ derives from the first three proteins in which these domains were identified: PSD-95 (a 95 kDa protein involved in signaling at the postsynaptic density), DLG (the Drosophila melanogaster Discs Large protein), and ZO-1 (the zonula occludens 1 protein involved in maintenance of epithelial polarity). PDZ domains function as protein-protein interaction modules. The first identified (and by far the most common) function of PDZ domains is the recognition of specific C-terminal motifs found in partner proteins, most often in the cytoplasmic tails of transmembrane receptors and channels.

Adenylyl cyclase activation is thought to be responsible for most cellular responses to PTH and PTHrP, although many actions appear to be independent of adenylyl cyclase. In the current study, researchers from Johns Hopkins University (Baltimore, MD, USA) and Harvard University (Boston, MA, USA) found that when NHERF2 is present along with the parathyroid hormone receptor, the signal is sent via calcium. If there is no NHERF2, then cAMP is responsible for delivering the message.

"The cell's decision to use calcium or cAMP is important because each generates different responses from its target proteins,” explained Dr. Mark Donowitz, professor of medicine at Johns Hopkins University and co-author of the study. "These results show that at the very earliest stage of cell signaling, called receptor binding, there is a switch that determines what kind of signal will be used. To understand cell signaling, you really have to know the whole system.”




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