Researchers from the Florida campus of the Scripps Research Institute say they have found that the RPM-1 protein plays a far more sophisticated role in neuron development than previously thought. Their study ("RPM-1 Uses Both Ubiquitin Ligase and Phosphatase-Based Mechanisms to Regulate DLK-1 during Neuronal Development"), published in PLOS Genetics, focuses on how this large, intracellular signaling protein harnesses sophisticated mechanisms to regulate neuron development.
Specifically, the research sheds light on the role of RPM-1 in the development of axons. Some axons are quite long; in the sciatic nerve, axons run from the base of the spine to the big toe.
"Collectively, our recent work offers significant evidence that RPM-1 coordinates how long an axon grows with construction of synaptic connections," said Brock Grill, Ph.D., assistant professor. "Understanding how these two developmental processes are coordinated at the molecular level is extremely challenging. We've now made significant progress."
The study describes how RPM-1 regulates the activity of a single protein known as DLK-1, which regulates neuron development and plays an essential role in axon regeneration. RPM-1 uses PPM-2, an enzyme that removes a phosphate group from a protein thereby altering its function, in combination with ubiquitin ligase activity to directly inhibit DLK-1.
"We identified protein phosphatase magnesium/manganese dependent 2 (PPM-2) as a novel RPM-1 binding protein. Genetic, transgenic, and biochemical studies indicated that PPM-2 functions coordinately with the ubiquitin ligase activity of RPM-1 and the F-box protein FSN-1 to negatively regulate DLK-1," wrote the investigators. "PPM-2 acts on S874 of DLK-1, a residue implicated in regulation of DLK-1 binding to a short, inhibitory isoform of DLK-1 (DLK-1S). Our study demonstrates that PHR [Pam/Highwire/RPM-1] proteins function through both phosphatase and ubiquitin ligase mechanisms to inhibit DLK. Thus, PHR proteins are potentially more accurate and sensitive regulators of DLK than originally thought. Our results also highlight an important and expanding role for the PP2C phosphatase family in neuronal development."
"Studies on RPM-1 have been critical to understanding how this conserved family of proteins works," noted Scott T. Baker, Ph.D., the first author of the study and a member of Dr. Grill's research team. "Because RPM-1 plays multiple roles during neuronal development, you wouldn't want to interfere with it. But exploring the role of PPM-2 in controlling DLK-1 and axon regeneration could be worthwhile and could have implications in neurodegenerative diseases."