Intracellular RET signaling pathways activated by GDNF
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REVIEW
Intracellular RET signaling pathways activated by GDNF Kumi Kawai 1 & Masahide Takahashi 2,3 Received: 20 March 2020 / Accepted: 20 July 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Activation of REarranged during Transfection (RET) proto-oncogene is responsible for various human cancers such as papillary and medullary thyroid carcinomas and non-small cell lung carcinomas. RET activation in these tumors is caused by point mutations or gene rearrangements, resulting in constitutive activation of RET tyrosine kinase. Physiologically, RET is activated by glial cell line–derived neurotrophic factor (GDNF) ligands that bind to coreceptor GDNF family receptor alphas (GFRαs), leading to RET dimerization. GDNF-GFRα1-RET signaling plays crucial roles in the development of the enteric nervous system, kidney and lower urinary tract as well as in spermatogenesis. Intracellular tyrosine phosphorylation in RET and recruitment of adaptor proteins to phosphotyrosines are essential for various biological functions. Significance of intracellular RET signaling pathways activated by GDNF is discussed and summarized in this review. Keywords RET . Oncogene . GDNF . GDNF family receptor α . Tyrosine phosphorylation . Intracellular signaling
REarranged during Transfection (RET) is a well-known protooncogene and has been implicated as a causative gene for several oncogenic and developmental disorders (Takahashi 2001). RET activating point mutations are detected in most hereditary medullary thyroid carcinomas and are strongly correlated to neuroendocrine tumors but are rarely found in cancers of other organ systems (Mulligan 2019). Another mechanism of ligand-independent RET activation is gene rearrangement, which results in oncogenic fusion genes. These RET fusions are found in papillary thyroid carcinomas and lung adenocarcinomas with a RET intracellular tyrosine kinase domain that is fused to the 5′ partner gene, which allows the fusion protein to localize in the cytoplasm and dimerize in the absence of ligands, thereby resulting in constitutive activation of the RET tyrosine kinase domain (Li et al. 2019a). In * Masahide Takahashi [email protected]; [email protected] Kumi Kawai [email protected] 1
Department of Pathology, Fujita Health University, 1-98 Kutsukake-cho, Dengakugakubo, Toyoake 470-1192, Japan
2
International Center for Cell and Gene Therapy, Fujita Health University, 1-98 Kutsukake-cho, Dengakugakubo, Toyoake 470-1192, Japan
3
Department of Pathology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
contrast, RET-inactivating mutations induce Hirschsprung’s disease (HSCR), which is a congenital abnormality of the enteric nervous system with a lack of ganglion cells in the rectum and colon. Over 100 RET mutations have been reported in HSCR cases, including large deletions, micro deletions, insertions, nonsense mutations, missense mutations and splicing mutations (Sergi et al. 2017). RET loss-of-fun
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