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 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.
Ledda
Fernanda
F
Laboratory of Molecular and Cellular Neuroscience, Department of Neuroscience, Karolinska Institute, 171 77 Stockholm, Sweden.
Bieraugel
Oliver
O
Fard
Shahrzad Shirazi
SS
Vilar
Marçal
M
Paratcha
Gustavo
G
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004622:Embryo, Mammalian; D004789:Enzyme Activation / Q000187:drug effects; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000494:pharmacology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology*; D021962:Membrane Microdomains / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D017783:Superior Cervical Ganglion / Q000166:cytology; D014162:Transfection
D051100:Glial Cell Line-Derived Neurotrophic Factor; C484445:LRIG1 protein, human; D008562:Membrane Glycoproteins; D009842:Oligopeptides; C090535:benzyloxycarbonyl-isoleucyl-glutamyl(O-tert-butyl)-alanyl-leucinal; D011505:Protein-Tyrosine Kinases; D051096:Proto-Oncogene Proteins c-ret; C495001:Ret protein, rat; C078846:epoxomicin