The RET (REarranged during Transfection) receptor is a transmembrane tyrosine kinase enzyme enzyme. RET forms a complex with members of the GPI-linked GDNF family receptors (GFR) to respond to GDNF family ligands, including glial cell-derived neurotrophic factors including glial cell-derived neurotrophic factor GDNF (GDNF, P39905) (211 aa); neurturin (NRTN, Q99748) (197 aa); artemin (ARTN, Q5T4W7) (237 aa) and persephin (PSPN, O60542) (156 aa). RET also forms a complex with GFRAL, which is activated by growth differentiation factor 15 (GDF15, Q99988) (GDF15) [5-6]. RET is involved in neural crest development. Loss of function mutations lead to Hirschprung's disease, while gain of function mutations lead to multiple endocrine neoplasias type 2A and 2B. There are isoforms - RET51 and RET9 - with distinct signalling properties.

A number of tyrosine kinase inhibitors targeting RET have been described [4], including selpercatinib, a RET inhibitor FDA-approved for non-small-cell lung cancer [3].

* Key recommended reading is highlighted with an asterisk

* Ibáñez CF, Paratcha G, Ledda F. (2020) RET-independent signaling by GDNF ligands and GFRα receptors. Cell Tissue Res, 382 (1): 71-82. [PMID:32737575]

* Ibáñez CF, Andressoo JO. (2017) Biology of GDNF and its receptors - Relevance for disorders of the central nervous system. Neurobiol Dis, 97 (Pt B): 80-89. [PMID:26829643]

* Sidorova YA, Saarma M. (2020) Small Molecules and Peptides Targeting Glial Cell Line-Derived Neurotrophic Factor Receptors for the Treatment of Neurodegeneration. Int J Mol Sci, 21 (18). [PMID:32911810]

* Wang D, Day EA, Townsend LK, Djordjevic D, Jørgensen SB, Steinberg GR. (2021) GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease. Nat Rev Endocrinol, 17 (10): 592-607. [PMID:34381196]

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2. Clemens GR, Schroeder RE, Magness SH, Weaver EV, Lech JW, Taylor VC, Masuda ES, Baluom M, Grossbard EB. (2009) Developmental toxicity associated with receptor tyrosine kinase Ret inhibition in reproductive toxicity testing. Birth Defects Res Part A Clin Mol Teratol, 85 (2): 130-6. [PMID:19107952]

3. Drilon A, Oxnard GR, Tan DSW, Loong HHF, Johnson M, Gainor J, McCoach CE, Gautschi O, Besse B, Cho BC et al.. (2020) Efficacy of Selpercatinib in RET Fusion-Positive Non-Small-Cell Lung Cancer. N Engl J Med, 383 (9): 813-824. [PMID:32846060]

4. Fabbro D, Cowan-Jacob SW, Möbitz H, Martiny-Baron G. (2012) Targeting cancer with small-molecular-weight kinase inhibitors. Methods Mol Biol, 795: 1-34. [PMID:21960212]

5. Mullican SE, Lin-Schmidt X, Chin CN, Chavez JA, Furman JL, Armstrong AA, Beck SC, South VJ, Dinh TQ, Cash-Mason TD et al.. (2017) GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Nat Med, 23 (10): 1150-1157. [PMID:28846097]

6. Yang L, Chang CC, Sun Z, Madsen D, Zhu H, Padkjær SB, Wu X, Huang T, Hultman K, Paulsen SJ et al.. (2017) GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand. Nat Med, 23 (10): 1158-1166. [PMID:28846099]