Ligand-Occupied Integrin Internalization Links Nutrient Signaling to Invasive Migration

Abstract

Integrin trafficking is key to cell migration, but little is known about the spatiotemporal organization of integrin endocytosis. Here, we show that α5β1 integrin undergoes tensin-dependent centripetal movement from the cell periphery to populate adhesions located under the nucleus. From here, ligand-engaged α5β1 integrins are internalized under control of the Arf subfamily GTPase, Arf4, and are trafficked to nearby late endosomes/lysosomes. Suppression of centripetal movement or Arf4-dependent endocytosis disrupts flow of ligand-bound integrins to late endosomes/lysosomes and their degradation within this compartment. Arf4-dependent integrin internalization is required for proper lysosome positioning and for recruitment and activation of mTOR at this cellular subcompartment. Furthermore, nutrient depletion promotes subnuclear accumulation and endocytosis of ligand-engaged α5β1 integrins via inhibition of mTORC1. This two-way regulatory interaction between mTORC1 and integrin trafficking in combination with data describing a role for tensin in invasive cell migration indicate interesting links between nutrient signaling and metastasis.

Behind the Scenes: Endo/Exocytosis in the Acquisition of Metastatic Traits

“…In low nutrient conditions, inhibition of mTORC1 results in the accumulation of a5b1 integrin on late endosomes/lysosomes, and in tumors characterized by a potentiated Rab25 circuitry, this might promote integrin recycling and cell invasion (21). Under similar conditions, Rab25 stimulates glucose uptake, through direct binding to and activation of AKT, resulting in higher glycogen synthesis and elevated ATP levels, thereby providing cancer cells with an alternative energy source (20).…”

“…This is the case of the Rab11 family effector, Rab coupling protein (RCP), CLIC3 and Tensin1 (21,24,25). The case of RCP is particularly interesting.…”

PPFIA1 drives active α5β1 integrin recycling and controls fibronectin fibrillogenesis and vascular morphogenesis

“…The importance of this process is highlighted by the severe impairment of FN fibrillogenesis that occurs in ECs on disruption of Nrp1 signaling14. Since internalized active α5β1 integrins recycle back to the cell surface1516, it has been proposed that they may also accomplish other tasks in addition to the endocytosis of FN fragments, such as the binding of newly synthesized FN in the exocytosis pathway, resulting in its deposition and polymerization at the basolateral surface of ECs to replenish degraded FN fibrils91014. Despite the attractiveness of this hypothesis and the fact that the turnover of the fibrillar FN network is essential for physiologic as well as pathologic angiogenesis, it is unknown where in the cell α5β1 integrins may be loaded with newly synthesized FN molecules and how the exocytosis of the FN-α5β1 integrin complex could be orchestrated at the molecular level.…”

Novel functions for integrin-associated proteins revealed by myofibril attachment inDrosophila

“…in!integrin!recycling!(e.g. !Rainero!et!al.,!2015) (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.…”