IVASKA LAB

Cell Adhesion and Cancer

Integrin Traffic

Introduction: The endocytic pathway is now recognised as an important mechanism to regulate receptor function, cell migration and tumour cell invasion and has been described for many receptors including RTKs (e.g. VEGF, EGF and PDGF) and other cell surface receptors such as syndecans. Integrin traffic represents a crucial mechanism whereby cells confer tight control over integrin signalling and facilitate differential expression of integrin heterodimers on the cell surface to elicit specific cellular responses.

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.

Our research: We have previously demonstrated a critical role for Rab21 small GTPase in the constitutive recycling of β1-integrins whereby Rab21 mediates receptor internalisation through direct binding to integrin α-tails (see Publications; Pellinen et al. 2006). Rab21 guides integrins from the plasma membrane to early endosomes, where it is displaced by p120RasGAP-integrin interaction triggering receptor recycling back to the plasma membrane (see Publications; Mai et al. 2011). The Rab21-mediated integrin endocytosis is also critical for normal cell cytokinesis as loss of Rab21 leads to the accumulation of multinucleated cells – one of the hallmarks of cancer (see Publications; Pellinen et al. 2008). More recently we showed distinct recycling pathways for integrin heterodimers based on the activation state of the molecule (see Publications; Arjonen et al. 2012). In addition to several projects focused on regulators of integrin traffic, identified in genomic screens, we are investigating RTK traffic and integrin and RTK crosstalk in cancer from a trafficking perspective (see Publications; Muharram et al. 2014).

An example of integrin trafficking pathways. Active integrins (extended ligand-bound receptors) and inactive integrins (bent conformation) are endocytosed via clathrin- and dynamin-dependent routes. The heterodimers are then recycled back to the plasma membrane via distinct mechanisms depending on their conformation. See Arjonen et al,. 2012.