Intersectin‐s interaction with DENND2B facilitates recycling of epidermal growth factor receptor

Abstract

Epidermal growth factor (EGF) activates the EGF receptor (EGFR) and stimulates its internalization and trafficking to lysosomes for degradation. However, a percentage of EGFR undergoes ligand-independent endocytosis and is rapidly recycled back to the plasma membrane. Importantly, alterations in EGFR recycling are a common hallmark of cancer, and yet, our understanding of the machineries controlling the fate of endocytosed EGFR is incomplete. Intersectin-s is a multi-domain adaptor protein that is required for internalization of EGFR Here, we discover that intersectin-s binds DENND2B, a guanine nucleotide exchange factor for the exocytic GTPase Rab13, and this interaction promotes recycling of ligand-free EGFR to the cell surface. Intriguingly, upon EGF treatment, DENND2B is phosphorylated by protein kinase D and dissociates from intersectin-s, allowing for receptor targeting to degradation. Our study thus reveals a novel mechanism controlling the fate of internalized EGFR with important implications for cancer.

Rab13 regulates sEV secretion in mutant KRAS colorectal cancer cells

“…One possibility is that DENND2B, a known GEF of Rab13, activates Rab13 via regulation by KRAS signaling 18 . DENND2B is down regulated by protein kinase D (PKD) 18,37 which is transcriptionally regulated by the KRAS-NF-κB signaling cascade in pancreatic cancer, suggesting that Rab13 may be functioning in a DENND2B-independent mechanism when regulating EV secretion in KRAS-mutant cells 38 . Further understanding of how KRAS activation drives Rab13-dependent EV secretion is required to determine the cellular contexts in which these EVs are regulated and released, and whether the affects we observe extend beyond colorectal cancer.…”

To degrade or not to degrade: mechanisms and significance of endocytic recycling

“…A role of phosphorylation in regulating the retrieval and recycling versus ligand-induced degradation has also been described for EGFR 104 . In the absence of EGF, the multidomain adaptor protein intersectin-s recycles the inactive EGFR by linking it to the RAB13 guanine nucleotide exchange factor DENND2B (DENN/MADD domain containing 2B) and a RAB13 dependent recycling route.…”

“…In the absence of EGF, the multidomain adaptor protein intersectin-s recycles the inactive EGFR by linking it to the RAB13 guanine nucleotide exchange factor DENND2B (DENN/MADD domain containing 2B) and a RAB13 dependent recycling route. Upon EGF induced EGFR activation this recycling is disrupted by protein kinase D-dependent phosphorylation of intersectin-s, which dissociates from DENND2B and switches the EGFR from the retrieval and recycling fate to a degradative fate 104 (it is presently unclear how this recycling pathway relates to retromer and retriever-mediated recycling). Importantly, the EGFR can also be activated by transforming growth factor-α (TGF-α).…”

The atypical Rho GTPase RhoU interacts with Intersectin-2 to regulate endosomal recycling pathways

“…Both Rabaptin-5 and KIF16B coordinate Rab5 and Rab4 for efficient vesicle recycling (Hoepfner et al, 2005;Pagano et al, 2004;Stenmark et al, 1995). Recently, ITSN1-S has been reported to localize to Rab4-positive vesicles (Gryaznova et al, 2018) and to interact with DENND2B, an exchange factor for Rab13 involved in EGF receptor recycling (Ioannou et al, 2017). ITSN1 knock-out mice showed only minor (Yu et al, 2008) or no defects (Sakaba et al, 2013) in CME-dependent synaptic vesicle recycling in neurons, but neurons have enlarged EEA1-endosomes (Yu et al, 2008).…”