Rit mutants confirm role of MEK/ERK signaling in neuronal differentiation and reveal novel Par6 interaction

Jennifer L. Rudolph; Geng Xian Shi; Eda Erdogan; Alan P. Fields; Douglas A. Andres

doi:10.1016/j.bbamcr.2007.09.008

Rit mutants confirm role of MEK/ERK signaling in neuronal differentiation and reveal novel Par6 interaction

Jennifer L. Rudolph
, Geng Xian Shi
, Eda Erdogan
, Alan P. Fields
, Douglas A. Andres

Producción científica: Article › revisión exhaustiva

17 Citas (Scopus)

Resumen

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.

Idioma original	English
Páginas (desde-hasta)	1793-1800
Número de páginas	8
Publicación	Biochimica et Biophysica Acta - Molecular Cell Research
Volumen	1773
N.º	12
DOI	https://doi.org/10.1016/j.bbamcr.2007.09.008
Estado	Published - dic 2007

Nota bibliográfica

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.

Financiación

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.

Financiadores	Número del financiador
American Lung Association/LUNGevity Foundation
James and Esther King Florida Biomedical Research Program
National Institutes of Health (NIH)	CA81436
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council	P20RR20171, R01NS045103
National Center for Research Resources
American the American Heart Association
U.S. Public Health Service	NS045103

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.bbamcr.2007.09.008

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title = "Rit mutants confirm role of MEK/ERK signaling in neuronal differentiation and reveal novel Par6 interaction",

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.",

keywords = "ERK MAP kinase, GTPase, Neuronal differentiation, PC12 cell, Par6, Ras, Rit",

author = "Rudolph, \{Jennifer L.\} and Shi, \{Geng Xian\} and Eda Erdogan and Fields, \{Alan P.\} and Andres, \{Douglas A.\}",

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.",

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language = "English",

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AU - Andres, Douglas A.

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PY - 2007/12

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N2 - 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.

AB - 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.

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Rit mutants confirm role of MEK/ERK signaling in neuronal differentiation and reveal novel Par6 interaction

Resumen

Nota bibliográfica

Financiación

ASJC Scopus subject areas

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