RET and Associated Diseases
With a long tradition of reputation and service, Creative Biolabs expands the capabilities of academic laboratories, biotechnology companies, and pharmaceutical companies. We work with our clients to ensure that the most effective and cost-effective protocols are developed for preclinical drug discovery and research.
Biological Characteristics of the RET Gene and Protein
The RET (rearranged during transfection) protooncogene is located in the pericentromeric region of chromosome 10q11.2 and spans 21 exons. RET protein is structured with an extracellular portion (which contains four cadherinlike repeats, a calcium-binding site, and a cysteine-rich region), a transmembrane portion, and an intracellular portion, which contains two tyrosine kinase subdomains (TK1 and TK2) that are involved in the activation of several intracellular signal transduction pathways. RET is the receptor for members of the glial cell-derived neurotrophic factor (GDNF) family of ligands (GFLs): namely GDNF, Neurturin, Persephin, and Artemin. On the cell membrane, RET is part of a multiprotein complex with glycosylphosphatidylinositol-linked proteins that functions as coreceptors. RET is expressed in neuroendocrine cells, including C-cells of the thyroid, the precursors of MTC, and in pheochromocytomas.
Fig.1 The RET receptor tyrosine kinase. (Mulligan, 2014)
Functions of RET
RET binds glial-derived neurotrophic factor (GDNF) family ligands with a co-receptor designated GDNF family receptor alpha (GFRα). RET signaling is essential for renal morphogenesis, the development of nerve and neuroendocrine tissues, and the maintenance of spermatogonial stem cells. It is required for the early induction of growth, branching, and morphogenesis of ureteral buds in the developing metanephric. RET also acts as a multifunctional guiding receptor for axon growth and targeting, and as a neuronal survival receptor for peripheral neurons of the adult brain and sympathetic and parasympathetic nervous systems. Tyrosine kinase receptor RET is a major gene with rare coding sequence mutations and/or frequent variants located in disease-prone enhancer elements. Known mutations in RET lead to autophosphorylation and increased function of tyrosine sites within RET and are directly related to the molecular pathophysiology of multiple endocrine tumors type 2 (MEN-2).
Expression of RET in Diseases
Various RET mutations have been identified and correlated with disease phenotype. RET mutations affect a variety of diseases in organ systems, from Hirschsprung and multiple endocrine neoplasias 2 (MEN2) to papillary thyroid carcinoma (PTC) and non-small cell lung cancer (NSCLC). RET mutations causative of MEN2 is called “gain of function” mutations since they cause ligand-independent RET activation and constitutive cell signaling. Loss-of-function mutations in the RET gene are associated with Hirschsprung’s disease (HSCR), a congenital disorder characterized by the absence of ganglia in the distal part of the gut, these mutations can prevent or impede the embryonic development of RET-dependant structures.
The use of drugs to target various tyrosine kinases (constituent-activated) has recently been successful against cancer. The gene therapy approach might be the introduction of a RET-selective ribozyme that specifically cuts mutant RET mRNA and blocks RET-mediated cell growth and transformation.
Creative Biolabs is a recognized expert in the early-stage drug discovery research market. In a dynamic environment, we have the will to keep up with the latest developments. We apply our deep knowledge to the progress of our clients' challenging projects. Please do not hesitate to contact us to further discuss your requirements.
Reference
- Mulligan, L.M. RET revisited: expanding the oncogenic portfolio. Nature Reviews Cancer. 2014, 14(3): 173-186.
