Jäntti, N. Z. | Search bioRxiv

bioRxiv2024

EPLINα controls integrin recycling from Rab21 endosomes to drive breast cancer cell migration

EPLIN, an actin-binding protein, has been described as both a tumour promoter and tumour suppressor in different cancers. EPLIN isoform( or {beta})-specific functions, which remain largely unknown, could explain these opposing roles. We observed distinct EPLIN-isoform localization; EPLIN is recruited to actin in plasma membrane ruffles and endosomes, while EPLIN{beta} resides on actin stress fibers. We identified two EPLIN actin-binding regions and demonstrated EPLIN interaction with Rab21, an established regulator of {beta}1-integrin endosomal traffic. EPLIN co-localizes with Rab21 and F-actin on recycling endosomes in an actin binding-dependent manner and supports {beta}1-integrin recycling and cell migration. Using BioID, we identified coronin 1C as an EPLIN proximal protein, which localizes at Rab21-containing endosomes in an EPLIN-dependent manner. EPLIN expression was linked to increased breast cancer cell motility, and high EPLIN-to-EPLIN{beta} ratio correlated with a mesenchymal phenotype in patient samples. Our work unveils unprecedented EPLIN isoform-specific functions relevant to breast cancer and beyond.

cell biology↗

bioRxiv2020

Cargo-specific recruitment in clathrin and dynamin-independent endocytosis

Spatially controlled, cargo-specific endocytosis is essential for development, tissue homeostasis, and cancer invasion and is often hijacked by viral infections 1. Unlike clathrin-mediated endocytosis, which exploits cargo-specific adaptors for selective protein internalization, the clathrin and dynamin-independent endocytic pathway (CLIC-GEEC, CG-pathway) has until now been considered a bulk internalization route for the fluid phase, glycosylated membrane proteins and lipids 2,3. Although the core molecular players of CG endocytosis have been recently defined, no cargo-specific adaptors are known and evidence of selective protein uptake into the pathway is lacking 3. Here, we identify the first cargo-specific adaptor for CG-endocytosis and demonstrate its clinical relevance in breast cancer progression. By combining unbiased molecular characterization and super-resolution imaging, we identified the actin-binding protein swiprosin-1 (EFHD2) as a cargo-specific adaptor regulating integrin internalization via the CG-pathway. Swiprosin-1 couples active Rab21-associated integrins with key components of the CG-endocytic machinery, IRSp53 and actin. Swiprosin-1 is critical for integrin endocytosis, but not for other CG-cargo and supports integrin-dependent cancer cell migration and invasion, with clinically relevant implications for breast cancer. Our results demonstrate a previously unknown cargo selectivity for the CG-pathway and opens the possibility to discover more adaptors regulating it.

cell biology↗