IBCN   20355
INSTITUTO DE BIOLOGIA CELULAR Y NEUROCIENCIA "PROFESOR EDUARDO DE ROBERTIS"
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Lrig1, a novel GDNF/ Ret signaling inhibitor.
Autor/es:
LEDDA, F.,; BIERÄUGEL, O. C.,; SHIRAZI FARD, S.,; VILAR, M.,; PARATCHA, G.,
Lugar:
Ginebra, Suiza.
Reunión:
Congreso; FENS Forum 2008; 2008
Institución organizadora:
Federation of European Neurosciences Societies (FENS)
Resumen:
The development of the nervous system is tightly regulated by neurotrophic factors. Glial cell line-derived neurotrophic factor (GDNF) /Ret signaling is a potent trophic factor for 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 (LRRs) and immunoglobulin-like domains in its extracellular region, acts in a negative feedback loop to regulate the activity of Ret receptor tyrosine kinase. We demonstrate that Lrig1 is capable of physically associate with Ret and that Lrig1/Ret interaction restricts GDNF binding, recruitment of Ret to lipid rafts, receptor autophosphorylation, and MAPK activation in response to GDNF. Lrig1 overexpression also inhibits GDNF/Ret-induced neurite outgrowth in a cell-autonomous manner. Downregulation of Lrig1 using small interference RNA knockdown 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 to GDNF.