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The Journal of Neuroscience, January 2, 2008, 28(1):39-49; doi:10.1523/JNEUROSCI.2196-07.2008

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

Fernanda Ledda,¹ Oliver Bieraugel,¹ Shahrzad Shirazi Fard,¹ Marçal Vilar,² and Gustavo Paratcha¹

¹Laboratory of Molecular and Cellular Neuroscience, Department of Neuroscience, Karolinska Institute, 171 77 Stockholm, Sweden, and ²Departament de Bioquimica i Biología Molecular, Universitat de Valencia, 46100 Burjassot, Spain

Correspondence should be addressed to Gustavo Paratcha, Laboratory of Molecular and Cellular Neuroscience, Department of Neuroscience, Karolinska Institute, Retzius väg 8, 171 77 Stockholm, Sweden. Email: gustavo.paratcha{at}ki.se

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.

Key words: GDNF; Ret; signaling mechanisms; Lrig1; RTK inhibitors; lipid rafts

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Received May 14, 2007; revised Oct. 9, 2007; accepted Oct. 15, 2007.

Correspondence should be addressed to Gustavo Paratcha, Laboratory of Molecular and Cellular Neuroscience, Department of Neuroscience, Karolinska Institute, Retzius väg 8, 171 77 Stockholm, Sweden. Email: gustavo.paratcha{at}ki.se

This article has been cited by other articles:

				V. E. Abraira, T. del Rio, A. F. Tucker, J. Slonimsky, H. L. Keirnes, and L. V. Goodrich Cross-repressive interactions between Lrig3 and netrin 1 shape the architecture of the inner ear Development, December 15, 2008; 135(24): 4091 - 4099. [Abstract] [Full Text] [PDF]

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