Copyright © Johanna Ivaska. All rights reserved.
More recently, using an evolutionary biology approach, we discovered a mechanism whereby integrin heterodimers can be selectively endocytosed, thus reducing their bioavailability for ECM engagement at a given time. Specifically, we identified an evolutionary preserved binding motif for the AP2 adaptor in several α-integrin subunits including 2 out of 4 collagen-binding integrins and one fibronectin-binding integrin heterodimer. Mutation of this AP2 motif resulted in defects in cell migration and cell spreading demonstrating that selective integrin turnover has a functional outcome on cell behaviour (see Publications; De Franceschi et al., 2015).
We also revealed, for the first time, that integrin signalling is not restricted to the plasma membrane as previously thought, but can be preserved during integrin endocytosis. These results are extremely exciting, particularly as integrins have been implicated as drivers of cancer cell migration, invasion and metastasis. Interestingly, the integrin-ECM signal initiated at the plasma membrane is prolonged and enhanced upon integrin endocytosis to EEA1-containing early endosomes. Integrin-induced FAK (focal adhesion kinase) activity within endosomes suppresses anoikis, thus supporting anchorage-independent growth of cancer cells and importantly cancer metastasis in vivo (see Publications; Alanko et al., 2015).
The cycle of receptor traffic primarily involves three steps: 1) invagination of the plasma membrane surrounding the receptor and formation of intracellular vesicles, 2) delivery of receptors to endosomal compartments for sorting, 3) targeting of receptors to either lysosomes for degradation or to recycling endosomes for redelivery back to the cell membrane and engagement of new ligand. Each of these steps can occur through multiple routes (e.g. clathrin-dependent or clathrin-independent endocytosis) and requires the spatial and temporal coordination of multiple molecules, including the Rho and Rab family of small GTPases, to precisely regulate receptor traffic and orchestrate cellular functions. We aim to understand the nature of the different pathways of integrin endocytosis and the conditions under which each pathway is activated in order to appreciate fully integrin-specific signalling in health and disease.