Liprin-α1 and ERC1 control cell edge dynamics by promoting focal adhesion turnover

Abstract

Liprin-α1 and ERC1 are interacting scaffold proteins regulating the motility of normal and tumor cells. They act as part of plasma membrane-associated platforms at the edge of motile cells to promote protrusion by largely unknown mechanisms. Here we identify an amino-terminal region of the liprin-α1 protein (liprin-N) that is sufficient and necessary for the interaction with other liprin-α1 molecules. Similar to liprin-α1 or ERC1 silencing, expression of the liprin-N negatively affects tumor cell motility and extracellular matrix invasion, acting as a dominant negative by interacting with endogenous liprin-α1 and causing the displacement of the endogenous ERC1 protein from the cell edge. Interfering with the localization of ERC1 at the cell edge inhibits the disassembly of focal adhesions, impairing protrusion. Liprin-α1 and ERC1 proteins colocalize with active integrin β1 clusters distinct from those colocalizing with cytoplasmic focal adhesion proteins, and influence the localization of peripheral Rab7-positive endosomes. We propose that liprin-α1 and ERC1 promote protrusion by displacing cytoplasmic adhesion components to favour active integrin internalization into Rab7-positive endosomes.

Liprin-α3 controls vesicle docking and exocytosis at the active zone of hippocampal synapses

“…Within neurons, Liprin-α1 is mostly localized dendritically, and knockdown and overexpression experiments support roles in dendrite morphogenesis (14,15,30). These functions are consistent with studies in nonneuronal cells, where Liprin-α1 controls edge dynamics in motile cancer cells through focal adhesion (31). Liprin-α2 localization appears more restricted to synapses, but, so far, it was unclear whether it is pre-or postsynaptically localized (14)(15)(16).…”

Assembly of the β4-Integrin Interactome Based on Proximal Biotinylation in the Presence and Absence of Heterodimerization*

“…We also investigated a couple of the highly ranked hits, ERC1 and UTRN, for their potential roles in laminin adhesions in more detail. ERC1 was recently reported to regulate FA turnover in a complex with Liprin-␣1 and LL5 (57). The LL5 complex in turn associates with integrin-mediated laminin adhesions in mammary epithelial cells, where it supposedly plays a role in the capture microtubules (58).…”

Liprin-β1 is upregulated in human hepatocellular carcinoma and is associated with advanced tumor stage

“…We propose that the functional divergence of liprin-β1 may be related to different interaction partners and subcellular localization in different cell types. For example, endogenous liprin-α1 and liprin-β1 colocalize near the protruding cell front and promote cell invasion by positively regulating the organization of lamellipodia and invadopodia [12,21,23], whereas liprin-β1 shows a diffuse distribution in the cytoplasm and plays inhibitory roles in the invasive behavior of cancer cells [10,24,25].…”

“…Notably, analysis of human cancers has revealed dysfunctions of the liprin proteins, with evidence pointing to the different roles of liprin family members in distinct aspects of tumor biology. For example, overexpression of liprin-α1 promotes breast cancer cell invasion by regulating lamellipodia stability and integrin-mediated focal adhesions [10,12]. By contrast, liprin-β2 impairs cell motility and suppresses tumor invasion, which is indicative of its role as a tumor suppressor [10].…”