Reactome | RET binds GFRA1,GFRA2

RET binds GFRA1,GFRA2

Stable Identifier

R-HSA-8871226

Type

Reaction [binding]

Species

Homo sapiens

Compartment

plasma membrane

ReviewStatus

5/5

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RET is a receptor tyrosine kinase with a cadherin-related motif and a cysteine-rich domain in the extracellular domain (Takahashi et al. 1988). It is the receptor for members of the glial cell-derived neurotrophic factor (GDNF) family of ligands (Lin et al. 1993, Kotzbauer et al. 1996, Baloh et al. 1998, Milbrandt et al. 1998). RET can only bind these ligands in the presence of a co-receptor from the family of glycosylphosphatidylinositol (GPI)-anchored co-receptors collectively termed GDNF family receptor-alpha (GFRA) (Treanor et al. 1996, Jing et al. 1996, Plaza-Menacho et al. 2006). Earlier models proposed that GDNF formed a complex with GFRA1 and subsequently recruited RET (Massagué et al. 1996). Current models suggest that GFRA and RET preassociate before ligand binding, based on binding and site-directed mutagenesis studies (Eketjäll et al. 1999, Cik et al. 2000). An alternative model suggests that GPI-anchored GFRA recruits RET to lipid rafts after GDNF stimulation (Tansey et al. 2000). The stoichiometry as well as the kinetics of ligand-receptor complex formation are not well understood. It is believed that all GDNF family members interact with their cognate co-receptor and activate RET in a similar manner to GDNF (Airaksinen & Saarma 2002).

Literature References

PubMed ID	Title	Journal	Year
9192684	Neurturin shares receptors and signal transduction pathways with glial cell line-derived neurotrophic factor in sympathetic neurons Creedon, DJ, Tansey, MG, Baloh, RH, Osborne, PA, Lampe, PA, Fahrner, TJ, Heuckeroth, RO, Milbrandt, J, Johnson, EM	Proc. Natl. Acad. Sci. U.S.A.	1997
9883723	Artemin, a novel member of the GDNF ligand family, supports peripheral and central neurons and signals through the GFRalpha3-RET receptor complex Baloh, RH, Tansey, MG, Lampe, PA, Fahrner, TJ, Enomoto, H, Simburger, KS, Leitner, ML, Araki, T, Johnson, EM, Milbrandt, J	Neuron	1998
8674117	GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-alpha, a novel receptor for GDNF Jing, S, Wen, D, Yu, Y, Holst, PL, Luo, Y, Fang, M, Tamir, R, Antonio, L, Hu, Z, Cupples, R, Louis, JC, Hu, S, Altrock, BW, Fox, GM	Cell	1996