Integrins are constantly recycled via the endosomal pathway and redistributed back to the cell surface to regulate cell adhesion dynamics and cell migration. β1 integrin recycling can occur through different routes, depending on its activation (conformational) state, but the underlying mechanisms that define these specific routes are poorly understood. Now, Ralph Böttcher and colleagues (Samarelli et al., 2020) identify the GTPase-activating protein Rabgap1 (also known as GAPCenA) as a key factor for the recycling of active β1 integrin. Rabgap1 binds to the proximal NPxY motif of the β1 integrin cytoplasmic tail through its phosphotyrosine-binding (PTB) domain. In addition, Rabgap1 and β1 integrin colocalize in early and recycling endosomes, but not in late endosomes or lysosomes. Rabgap1-depleted mouse fibroblasts show an overactivation of Rab11, a known target of Rab1gap1; this impairs the recycling of active β1 integrin from early endosomes, resulting in a decrease of active β1 integrin at the cell surface and leading to increased cell spreading and defective cell migration. Finally, depletion of Rabgap1 in the carcinoma cell line MDA-MB-231 diminishes cell migration and invasion capability in a 3D cell culture assay. Taken together, these data uncover Rabgap1 as a regulator of selective β1 integrin recycling, by modulating Rab11 activity, and an important factor for β1 integrin-mediated cancer cell invasion.
