Neurotrophic Factors

S.Q. Jing, D.Z. Wen, Y.B. Yu, P.L. Hoist, Y. Luo, M. Fang, R. Tamir, L. Antonio, Z. Hu, R. Cupples, J. Louis, S. Hu, B.W. Altrock, G.M. Fox, "GDNF-induced activation of the Ret protein tyrosine kinase is mediated by GDNFR-alpha, a novel receptor for GDNF," Cell, 85:1113-24, 1996. (Cited more than 170 times since publication) Comments made by Gary M. Fox, Department of Molecular Genomics, Amgen Inc., Thousand Oaks, Calif. Gary M. Fox, left, and Shuqian Jing Below the spatula and to the left is the substantia nigra, the area that degenerates in Parkinson's disease and the target sight for GDNF. Neurotrophic factors, human proteins that protect and promote the growth of certain nerve cells, have garnered much attention from researchers recently. And for good reason: They're believed to have the potential to halt--or, in some cases, even reverse--the nerve damage that can result from neurodegenerative diseases. One such protein, called glial cell derived neurotrophic factor (GDNF), is, for example, considered to be a possible therapeutic agent for Parkinson's disease and amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease. The authors of this paper, a team from Amgen Inc., a biotechnology company in Thousand Oaks, Calif., initially set out to investigate the mechanism of GDNF action. The group, led by Shuqian Jing, a research scientist in the department of molecular genomics at Amgen, cloned the GDNF receptor in hopes of better understanding tissue distribution of the GDNF receptor, the possible side effects of the GDNF, and other potential uses of the protein. However, their findings demonstrated something that was, according to senior author Gary M. Fox, "considerably more interesting." Because GDNF is related to ligand families such as transforming growth factor ß (TGFß) superfamily, and because the known receptors for this family are usually serine threonine kinases, that's precisely the sort of receptor that Fox and his team expected to clone. "What we got was something that didn't look like a kinase at all," reports Fox, the laboratory head for the department of molecular genomics at Amgen. "In fact, [it] turned out to be a binding component with no intracellular domain that could be responsible for transmembrane signaling." These findings prompted Jing and Fox to continue to search for additional components of the receptor that could explain its signaling mechanism. Other studies by other research teams helped solve the mystery. A Ret protein-tyrosine kinase (PTK) knockout experiment done by a group from Columbia University in 1994 (A. Schuchardt et al., Nature, 367:380-3, 1994), investigators produced mice that had renal agenesis (kidney failure) and lacked intestinal neurons throughout their digestive tracts. Jing would discover at a February 1996 meeting that several GDNF knockout experiments, the results of which had not yet been published (M.P. Sanchez, Nature, 382:70-3, 1996), had produced mice with strikingly similar phenotypes. These findings led many to believe that Ret was the receptor for GDNF. This, however, was not quite the case--and only two research teams knew it: The Amgen team, and a team from Genentech, a biotechnology company in South San Francisco, Calif. Jing and Fox surmised that their research into the biology of GDNF had actually revealed a novel cell surface receptor involved in the pathway: a receptor dubbed GDNFR-alpha or GFRalpha-1. As reported in this paper and, soon after, in one by the Genentech group (J.J. Treanor et al., Nature, 382:80-3, 1996), both teams had discovered that Ret PTK will only bind GDNF in the presence of GFRalpha-1. Previously, the biological action of receptor PTKs was thought to always be triggered by direct binding of their ligands, which in turn induced dimerization (or oligomerization), which then caused transmembrane signaling. "I think that probably the most important part of the paper turned out to be that it suggested receptor PTKs could work by an alternate mechanism," maintains Fox. "I think everyone assumed that all kinases provided their own ligand binding specificity rather than considering the possibility that they could function as the signaling component of a larger receptor complex." Jing and Fox have followed up their research with a 1997 paper that details the discovery of two related receptors, GFRalpha-2 and GFRalpha-3. Currently, they're doing knockouts of these receptors in order to elucidate their function.

Neurotrophic Factors

The Scientist Staff

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