Abstract
Rit is a novel member of the Ras superfamily of small GTP-binding proteins that regulates signaling pathways controlling cellular fate determination. Constitutively activated mutants of Rit induce terminal differentiation of pheochromocytoma (PC6) cells resulting in a sympathetic neuron-like phenotype characterized by the development of highly-branched neurites. Rit signaling has been found to activate several downstream pathways including MEK/ERK, p38 MAPK, Ral-specific guanine nucleotide exchange factors (GEFs), and Rit associates with the Par6 cell polarity machinery. In this study, a series of Rit effector loop mutants was generated to test the importance of these cellular targets to Rit-mediated neuronal differentiation. We find that Rit-mediated neuritogenesis is dependent upon MEK/ERK MAP kinase signaling but independent of RalGEF activation. In addition, in vivo binding studies identified a novel mechanism of Par6 interaction, suggesting that the cell polarity machinery may serve to spatially restrict Rit signaling.
| Original language | English |
|---|---|
| Pages (from-to) | 1793-1800 |
| Number of pages | 8 |
| Journal | Biochimica et Biophysica Acta - Molecular Cell Research |
| Volume | 1773 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 2007 |
Bibliographical note
Funding Information:This work was supported by Public Health Service grant NS045103 (to D.A.A) from the National Institute of Neurological Disorders and Stroke, by Grant P20RR20171 from the COBRE program of the National Center for Research Resources, a Predoctoral Fellowship from the Ohio Valley Affiliate of the American Heart Association (to J.L.R.), the National Institutes of Health (CA81436 to A.P.F), The James and Esther King Biomedical Research Program and the American Lung Association/LUNGevity Foundation (to A.P.F.). We thank Dr. Ian Macara for the generous gift of reagents.
Funding
This work was supported by Public Health Service grant NS045103 (to D.A.A) from the National Institute of Neurological Disorders and Stroke, by Grant P20RR20171 from the COBRE program of the National Center for Research Resources, a Predoctoral Fellowship from the Ohio Valley Affiliate of the American Heart Association (to J.L.R.), the National Institutes of Health (CA81436 to A.P.F), The James and Esther King Biomedical Research Program and the American Lung Association/LUNGevity Foundation (to A.P.F.). We thank Dr. Ian Macara for the generous gift of reagents.
| Funders | Funder number |
|---|---|
| American Lung Association/LUNGevity Foundation | |
| James and Esther King Florida Biomedical Research Program | |
| National Institutes of Health (NIH) | CA81436 |
| National Institute of Neurological Disorders and Stroke | P20RR20171, R01NS045103 |
| National Center for Research Resources | |
| American Heart Association | |
| U.S. Public Health Service | NS045103 |
Keywords
- ERK MAP kinase
- GTPase
- Neuronal differentiation
- PC12 cell
- Par6
- Ras
- Rit
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology