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

Abstract

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.

Regulation of epidermal growth factor receptor signalling by inducible feedback inhibitors

“…For example, MET signalling is inhibited by both LRIG1 (Shattuck et al, 2007) and RALT (Pante et al, 2005). LRIG1 is also capable of suppressing RET signalling (Ledda et al, 2008). These data are interesting in light of the fact that functional and/or physical interactions between MET and ErbB RTKs (Jo et al, 2000;Scheving et al, 2002;Engelman et al, 2007), as well as between RET and the EGFR (Croyle et al, 2008), have been reported.…”

Lrig1 is a cell‐intrinsic modulator of hippocampal dendrite complexity and BDNF signaling

“…MN1 is an immortalized mouse-derived motor neuron cell line expressing Lrig1 that was cultured in DMEM supplemented with 7.5% FBS [24]. BDNF was purchased from R&D Systems (Abingdon, UK) and MG-132 was from Calbiochem.…”

“…adhesion molecules or modulating neurotrophic growth factor receptor signaling during neural development [15,24,42]. Working in trans as cell adhesion molecules, many LRR transmembrane proteins affect axonal extension, guidance, target selection, and synapse formation [15,[43][44][45][46].…”

Driving GDNF expression: The green and the red traffic lights

“…4). Lrig1, a transmembrane protein containing leucine-rich repeats and Ig-like domains, interacts with Ret thereby inhibiting its recruitment to lipid rafts, the binding to the GDNF-GFRa1 complex, receptor autophosphorylation, and MAPK activation in response to GDNF (Ledda et al, 2008). Growth Arrest Specific 1 (Gas1) is a molecule involved in cell cycle arrest and widely expressed during development, but also induced during, and participating in, excitotoxic neuronal death (Mellstrom et al, 2002).…”