Lrig1 Is an Endogenous Inhibitor of Ret Receptor Tyrosine Kinase Activation, Downstream Signaling, and Biological Responses to GDNF

Glial cell line-derived neurotrophic factor (GDNF)/Ret signaling has potent trophic effects on ventral midbrain dopaminergic, motor, sensory, and sympathetic neurons. The molecular mechanisms that restrict Ret receptor tyrosine kinase activation are not well understood. Here, we show that Lrig1, a t...

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Published in:The Journal of neuroscience 2008-01, Vol.28 (1), p.39-49
Main Authors: Ledda, Fernanda, Bieraugel, Oliver, Fard, Shahrzad Shirazi, Vilar, Marcal, Paratcha, Gustavo
Format: Article
Language:English
Subjects:
Animals
Cell Differentiation - drug effects
Cell Survival
Cells, Cultured
Cercopithecus aethiops
Embryo, Mammalian
Enzyme Activation - drug effects
Glial Cell Line-Derived Neurotrophic Factor - pharmacology
Humans
Medicin och hälsovetenskap
Membrane Glycoproteins - physiology
Membrane Microdomains - drug effects
Neurons - drug effects
Neurons - metabolism
Oligopeptides - pharmacology
Protein Binding - drug effects
Protein-Tyrosine Kinases - metabolism
Proto-Oncogene Proteins c-ret - physiology
Rats
Rats, Sprague-Dawley
Signal Transduction - drug effects
Superior Cervical Ganglion - cytology
Transfection
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Summary:Glial cell line-derived neurotrophic factor (GDNF)/Ret signaling has potent trophic effects on ventral midbrain dopaminergic, motor, sensory, and sympathetic neurons. The molecular mechanisms that restrict Ret receptor tyrosine kinase activation are not well understood. Here, we show that Lrig1, a transmembrane protein containing leucine-rich repeats and Ig-like domains in its extracellular region, acts in a negative feedback loop to regulate the activity of Ret receptor tyrosine kinase. In particular, we demonstrate that Lrig1 is capable of physically interacting with Ret and that Lrig1/Ret association inhibits GDNF binding, recruitment of Ret to lipid rafts, receptor autophosphorylation, and mitogen-activated protein kinase (MAPK) activation in response to GDNF. In neuronal cells, Lrig1 overexpression also inhibits GDNF/Ret-induced neurite outgrowth in a cell-autonomous manner. Downregulation of Lrig1 using small interference RNA knock-down experiments potentiates both neuronal differentiation and MAPK activation in response to GDNF. Together, these results provide an insight into Lrig1 function and establish a new physiological mechanism to restrict signaling and biological responses induced by GDNF and Ret in neuronal cells.
ISSN:0270-6474
1529-2401
1529-2401
DOI:10.1523/JNEUROSCI.2196-07.2008