RET receptor signaling: Function in development, metabolic disease, and cancer

Abstract

The RET proto-oncogene encodes a receptor tyrosine kinase whose alterations are responsible for various human cancers and developmental disorders, including thyroid cancer, non-small cell lung cancer, multiple endocrine neoplasia type 2, and Hirschsprung's disease. RET receptors are physiologically activated by glial cell line-derived neurotrophic factor (GDNF) family ligands that bind to the coreceptor GDNF family receptor , (GFR,). Signaling via the GDNF/ GFR,1/RET ternary complex plays crucial roles in the development of the enteric nervous system, kidneys, and urinary tract, as well as in the self-renewal of spermatogonial stem cells. In addition, another ligand, growth differentiation factor-15 (GDF15), has been shown to bind to GFR,-like and activate RET, regulating body weight. GDF15 is a stress response cytokine, and its elevated serum levels affect metabolism and anorexia-cachexia syndrome. Moreover, recent development of RET-specific kinase inhibitors contributed significantly to progress in the treatment of patients with RET-altered cancer. This review focuses on the broad roles of RET in development, metabolic diseases, and cancer.

Association of rs2435357 and rs2506030 polymorphisms in RET with susceptibility to hirschsprung disease: A systematic review and meta-analysis

“…Using the (33). In addition, there is sufficient evidence that RET plays an important role in other developmental and metabolic disorders (42).…”

“…Using the strategy of combining gene-gene interaction analysis with case-control study, Wang et al demonstrated for the first time that the genetic markers of RET , ARHGEF3 , and CTNNAL1 and the related genetic interaction network can change the susceptibility risk of HSCR in the Han population ( 33 ). In addition, there is sufficient evidence that RET plays an important role in other developmental and metabolic disorders ( 42 ).…”

Targeted therapy of RET fusion-positive non-small cell lung cancer

“…RET protein has a tyrosine kinase intracellular domain linked to an outer cysteine-rich extracellular domain and four cadherin-like domains through transmembrane ( 16 , 17 ). The RET gene forms a ternary complex with Glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) and GDNF family co-receptors (GFR α1-4) leading to autophosphorylation of RET-intracellular domain, which activates downstream signaling pathways like PI3K/AKT, RAS/MAPK, JAK/STAT, and PKA/PKC, whose activation or inhibition has an important impact in cell survival, proliferation, migration, and differentiation ( 18 , 19 ). Figure 1 illustrates the constitutive patterns of the RET proteins.…”

RET Proto-Oncogene—Not Such an Obvious Starting Point in Cancer Therapy

“…RET is a transmembrane receptor tyrosine kinase, which is coded by proto-oncogene RET , and was first discovered in T cell lymphoma [ 3 ]. In normal cells, RET is involved in the process of fetal development of hematopoietic, genitourinary, gastrointestinal, and nervous systems.…”

“…While gene fusions are more common in papillary thyroid carcinoma (PTC), in around 10–20% of patients, they are much less common in non-small cell lung cancer (NSCLC), in around 1–2% of patients. On the other hand, point mutations in RET gene are common in sporadic medullary thyroid cancer (MTC), in 60–90% of patients, and in multiple endocrine neoplasia syndrome type 2 (MEN2) [ 3 , 4 , 5 ].…”