Expression of the receptor tyrosine kinase Ret on the plasma membrane is dependent on calcium

Abstract

Mutations in the Ret receptor tyrosine kinase are responsible for a variety of human syndromes, including multiple endocrine neoplasia 2 and Hirschsprung's disease. Ret is expressed as a 150-kDa precursor form in the endoplasmic reticulum and a 170-kDa mature form at the plasma membrane. Here we show that expression of p170ret is dependent on calcium. Depletion of extracellular calcium completely blocks p170ret expression, which is not caused by a decrease in half-life of p170ret at the plasma membrane but by a defect in processing of p150ret into p170ret. This processing defect can be mimicked by treating the cells with thapsigargin, a drug that releases calcium from internal stores, indicating that reduction in luminal calcium is responsible for the processing defect. We propose that a relatively high concentration of luminal calcium is necessary for the proper folding of Ret in the endoplasmic reticulum.