LRRK1 functions as a scaffold for PTP1B-mediated EGFR sorting into ILVs at the ER-endosome contact site.

Proper control of epidermal growth factor receptor (EGFR) signaling is important for maintaining cellular homeostasis. Since EGFR signaling occurs at the plasma membrane and endosomes following internalization, endosomal trafficking of EGFR regulates EGFR signaling spatiotemporally. In this process, leucine-rich repeat kinase 1 (LRRK1) has multiple roles in kinase activity-dependent transport of EGFR-containing endosomes and kinase-independent sorting of EGFR into the intraluminal vesicles (ILVs) of multivesicular bodies. Active EGFR inactivates the LRRK1 kinase activity by phosphorylating Tyr-944. In this study, we demonstrate that LRRK1 facilitates EGFR dephosphorylation by PTP1B, an endoplasmic reticulum (ER)-localized protein tyrosine phosphatase, at the ER-endosome contact site, after which EGFR is sorted into the ILVs of endosomes. LRRK1 is required for the PTP1B-EGFR interaction in response to EGF stimulation, resulting in the down-regulation of EGFR signaling. Furthermore, PTP1B activates LRRK1 by dephosphorylating pTyr-944 on the contact site, which promotes the transport of EGFR-containing endosomes. These findings provide evidence that the ER-endosome contact site functions as a hub for LRRK1-dependent signaling that regulates EGFR trafficking.