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Abstract
The intracellular trafficking of growth factor receptors determines the activity of their downstream signaling pathways. Here, we show that the putative HSP-90 co-chaperone CHP-1 acts as a regulator of EGFR trafficking in C. elegans. Loss of chp-1 causes the retention of the EGFR in the ER and decreases MAPK signaling. CHP-1 is specifically required for EGFR trafficking, as the localization of other transmembrane receptors is unaltered in chp-1(lf) mutants, and the inhibition of hsp-90 or other co-chaperones does not affect EGFR localization. The role of the CHP-1 homolog CHORDC1 during EGFR trafficking is conserved in human cells. Analogous to C. elegans, the response of CHORDC1-deficient A431 cells to EGF stimulation is attenuated, the EGFR accumulates in the ER and ERK2 activity decreases. Although CHP-1 has been proposed to act as a co-chaperone for HSP90, our data indicate that CHP-1 plays an HSP90-independent function in controlling EGFR trafficking through the ER.
Highlights
The generation and maintenance of cellular polarity is essential for the development and homeostasis of organs
We show that a loss of chp-1 function in C. elegans leads to the accumulation of LET-23 EGFR in the endoplasmic reticulum (ER) of the vulval precursor cells (VPCs), resulting in a strongly reduced activity of the RAS/MAPK pathway
In late L2/early L3 larvae before the VPCs have started dividing, a translational LET-23::GFP reporter was up-regulated in the 1 ̊ VPC P6.p, while expression faded in the other, more distal VPCs
Summary
The generation and maintenance of cellular polarity is essential for the development and homeostasis of organs. Cell polarity governs various processes, such as cell migration, asymmetric cell division and morphogenesis (Bryant and Mostov, 2008). Most of these processes are regulated by extracellular signals, which are received and transduced by specific receptors on the plasma membrane. The EGFR family of receptor tyrosine kinases, which are activated by a multitude of ligands, play essential roles during the development of most epithelial organs (Citri and Yarden, 2006; Sorkin and Goh, 2009). Caenorhabditis elegans expresses only one EGFR homolog, LET-23, and a single EGF family ligand, LIN-3 (Sundaram, 2006). The 3 ̊ VPCs divide once before fusing to the hypodermis
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