The CHORD protein CHP-1 regulates EGF receptor trafficking and signaling inC. elegansand in human cells

Abstract

AbstractThe intracellular trafficking of growth factor receptors determines the activity of their downstream signaling pathways. The putative co-chaperone CHP-1 acts as a regulator of EGFR trafficking duringC.elegansvulval development. Loss ofchp-1causes the retention of the EGFR in the ER and decreased MAPK signaling. CHP-1 functions specifically, as the localization of other receptors is unaltered inchp-1(lf)mutants, and inhibiting other co-chaperones does not affect EGFR localization. The role of CHP-1 during EGFR trafficking is conserved in humans. Analogous toC.elegans, the response of CHP-1-deficient human cells to EGF stimulation is attenuated, the EGFR accumulates in the ER and ERK2 activity is decreased. Although CHP-1 has been proposed to act as a co-chaperone for HSP90, our data indicate an HSP90-independent function of CHP-1. The identification of CHP-1 as a regulator of EGFR trafficking opens the possibility to identify small molecule chaperone inhibitors targeting the EGFR pathway with increased selectivity.