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. 2018 Apr 4;19(4):1078. doi: 10.3390/ijms19041078

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© 2018 by the authors.

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

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The interaction of glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) with their receptors. Four homodimeric GFLs (GDNF, NRTN, ARTN, and PSPN) recognize their corresponding GDNF family receptor α (GFRα/GFRA1-4). GDNF specifically binds to GFRA1, NRTN to GFRA2, ARTN to GFRA3, and PSPN to GFRA4. Dotted arrow indicates cross-interaction of GFLs with GFRA which has been observed. Binding of GFL with GFRA activates protein tyrosine kinase RET. Neural cell adhesion molecule (NCAM) has been identified as an alternative signaling receptor for GFLs. RET also has been known as the representative receptor tyrosine kinases (RTKs) for these neurotrophic factor receptors. Activation of RET or NCAM via the GFL/GFRA complex is involved in various physiological functions, such as neuronal cell growth, differentiation, migration, and osteosarcoma chemoresistance via autophagy. Gray-colored area of the membrane indicates lipid raft. NRTN, neurturin; ARTN, artemin; PSPN, persephin.