EXPRESSION OF THE RECEPTOR TYROSINE KINASE RET ON THE PLASMA-MEMBRANEIS DEPENDENT ON CALCIUM

Mutations in the Ret receptor tyrosine kinase are responsible for a va riety of human syndromes, including multiple endocrine neoplasia 2 and Hirschsprung's disease. Ret is expressed as a 180-kDa precursor form in the endoplasmic reticulum and a 170-kDa mature form at the plasma m embrane. Here we show that expression of p170(ret) is dependent on cal cium. Depletion of extracellular calcium completely blocks p170(ret) e xpression, which is not caused by a decrease in half-life of p170(ret) at the plasma membrane but by a defect in processing of p150(ret) int o p170(ret). This processing defect can be mimicked by treating the ce lls with thapsigargin, a drug that releases calcium from internal stor es, indicating that reduction in luminal calcium is responsible for th e processing defect. We propose that a relatively high concentration o f luminal calcium is necessary for the proper folding of Bet in the en doplasmic reticulum.