Migration cues interpretation by clathrin-coated structures
Introduction
Cell migration is an important aspect of cells' and organisms' physiology and pathology. It occurs in single-celled organisms seeking food or specific niches, but also in multi-cellular organisms in which it is instrumental during embryogenesis, immune response, physiological renewal of many different tissues and pathologies such as cancers [1]. Actin polymerization and/or actomyosin fibers contraction is a universal mechanism powering cell locomotion [2]. Yet, this engine needs to be regulated very precisely to organize it so that it leads to coordinated movements. Of major importance is the capacity of cells to migrate in a precise direction to reach a meaningful outcome. To achieve this, the cell reads and decodes information from its environment and accordingly tunes its migration machinery to produce a movement in a given direction. Immune cells chasing pathogens or amoeba migrating towards a food source represent obvious examples of how significant directed locomotion is. The general concept supporting the observed directed movements is that the environment produces gradients of different cues [3]. For instance, a focal source of food generates a gradient that fades away as a function of the distance from that source. Several types of gradients can be found in a given environment, including, but not limited to, gradients of soluble factors, gradients of extracellular matrix components and gradients of substrate rigidity. Cells can sense and interpret such gradients and reorganize their migration machinery to persistently migrate up, or sometimes down, the gradient [4]. In most cases, cell surface receptors represent the first line of extracellular signal detection. Factors that compose a gradient can activate specific receptors leading to intracellular signal transduction events that sculpt the actin machinery to polarize the cell in a given direction and produce a directed movement. Thus, regulation of these receptors is a key issue for cells to migrate in a directed manner.
Endocytosis is a fundamental process that regulates cell surface receptor uptake with important consequences on the availability, distribution, and activity of these receptors [5]. Clathrin-mediated endocytosis (CME) is the major internalization pathway and regulates the uptake of a diverse range of receptors [6]. CME relies on the formation of clathrin-coated structures (CCSs) at the internal leaflet of the plasma membrane. The coat of clathrin is composed of clathrin itself, as well as several adaptors that link clathrin to the membrane and recruit receptors into CCSs [6]. As CCSs assemble at the plasma membrane and recruit receptors, they progressively bend the membrane to produce receptor-containing vesicles that bud into the cytosol [7]. Besides canonical CCSs that produce vesicles, a subset of CCSs, called clathrin-coated plaques, are large, flat, and long-lived structures that do not seem to directly generate endocytic vesicles at a steady-state [8]. However, many clathrin-coated vesicles can be found at the rim of plaques suggesting that these structures may participate in organizing CME [9]. CME impacts receptor physiology in several ways. It controls the level of surface expression of these receptors but also their distribution by retrieving them from specific locations and allowing their recycling to other regions of the plasma membrane. CME also impacts the strength, duration, and quality of signaling events triggered by receptors [10]. Finally, an underestimated aspect through which CCSs regulate receptors is clustering them at the cell surface and offering platforms for the recruitment of specific adaptors [6]. These endocytosis-independent functions of CCSs are beginning to emerge as important regulators of cell adhesion and receptor signaling. Here, by focusing on cells migrating as single cells, we summarize recent findings on how CME and CCSs help cells decode and interpret signals from the environment to promote directed locomotion.
Section snippets
General organization of CME in migrating cells
In non-migrating cells, CCSs nucleate at random positions of the plasma membrane [11] and are consequently distributed all over the cell. However, several groups have reported that CCSs are enriched at the leading edge of cells migrating as single cells [12, 13, 14, 15] (Figure 1a). The mechanisms regulating this asymmetric distribution are not clear, but membrane tension may play a role. Indeed, it has been proposed that migrating cells exhibit a front/rear membrane tension gradient [16], with
Interpretation through cargo endocytosis
Cell surface receptors are instrumental in sensing cues that regulate cell migration. In mesenchymal-like migration, adhesion is required for the cell to transmit actin-generated forces to the substrate and thus to migrate. In most cases, adhesion to the extracellular matrix is mediated by integrins, and most integrins are well documented to be internalized through CME [23,24]. An attractive model proposed that CME would retrieve integrins from the cell back to allow their recycling at the cell
Endocytosis-independent signal interpretation
Besides the main role of CCSs in regulating receptors internalization, different investigators observed that these structures impact cell physiology independently of endocytosis. The key feature endowing CCSs with non-endocytic related functions seems to be their capacity to serve as platforms for the recruitment of receptors and/or specific regulators. For instance, it was shown that optimal EGFR signaling requires CCSs and the recruitment of the EGFR effector Gab1 at CCSs but is not modulated
Outlook
The role of CME in cell migration has long been acknowledged, but it is becoming clear that endocytosis is not the only way through which CCSs help the cell interpret signals from its environment and navigate through. CCSs are remarkably plastic and amenable structures able to dynamically organize the plasma membrane into discrete clusters of receptors and regulators. In addition, they are responsive to mechanical and topological cues and can also be regulated individually by local receptors
Conflict of interest statement
Nothing declared.
Acknowledgement
Core funding for this work was provided by the Gustave Roussy Institute and the Inserm and additional support was provided by grants from Institut Nationale du Cancer (INCA 2018-1-PL BIO-02-IGR-1) and the Fondation pour la Recherche Médicale (FRM DEQ20180339205) to GM.
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