Premium
Analysis of RET co‐receptor mutants in receptor activation
Author(s) -
Vega Quinn C.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.884.4
Subject(s) - proto oncogene proteins c ret , glial cell line derived neurotrophic factor , receptor , multiple endocrine neoplasia type 2 , mutant , neurturin , 5 ht5a receptor , receptor tyrosine kinase , enzyme linked receptor , interleukin 21 receptor , tropomyosin receptor kinase c , biology , microbiology and biotechnology , receptor protein tyrosine kinases , transfection , cancer research , mutation , genetics , gene , neurotrophic factors , platelet derived growth factor receptor , germline mutation , growth factor
RET is a mammalian receptor tyrosine kinase required for both proper neuronal and kidney development. Mutations in the ret gene are associated with Multiple Endocrine Neoplasia (MEN) 2A, MEN 2B and Familial Medullary Thyroid Carcinoma (FMTC) as well as Hirschsprung's Disease, a disease characterized by disruption in neuronal development. Wild type RET is activated after association with a membrane associated co‐receptor GFR‐α (1‐4) and its corresponding ligand (GDNF, Neurturin, Artemin or Persephin). In order to further understand the mechanism by which the co‐receptors activate RET, mutations were made in GFRa‐1 and the resulting mutants analyzed for their ability to activate RET. Mutations were made based on previous studies and through a comparison of co‐receptor sequences. Using a RET dependent luciferase reporter gene assay, specific co‐receptor mutants were transfected into NB41A3 cells and RET activity measured in the presence or absence of GDNF. Although wild type GFRα‐1 was able to increase luciferase activity in the presence of GDNF, individual co‐receptor mutants could not activate the receptor. Specifically, point mutations and insertion mutations in the center of the co‐receptor were able to disrupt co‐receptor activity. This decrease in activity was not due to decreased expression of the co‐receptor.