Spoiled for Choice: Diverse Endocytic Pathways Function at the Cell Surface

Abstract

Endocytosis has long been identified as a key cellular process involved in bringing in nutrients, in clearing cellular debris in tissue, in the regulation of signaling, and in maintaining cell membrane compositional homeostasis. While clathrin-mediated endocytosis has been most extensively studied, a number of clathrin-independent endocytic pathways are continuing to be delineated. Here we provide a current survey of the different types of endocytic pathways available at the cell surface and discuss a new classification and plausible molecular mechanisms for some of the less characterized pathways. Along with an evolutionary perspective of the origins of some of these pathways, we provide an appreciation of the distinct roles that these pathways play in various aspects of cellular physiology, including the control of signaling and membrane tension.

The role of lipid species in membranes and cancer-related changes

“…However, reducing the CHOL levels in cells by extraction of CHOL using mβCD will not only affect the structure and uptake via caveolae, but also result in perturbation of clathrinmediated endocytosis accompanied by formation of flat or shallow clathrin pits [95,96]. Also, macropinocytosis is strongly reduced by mβCD extraction of CHOL [97,98], and in fact most endocytic pathways can be expected to be affected by the CHOL level [72,99].…”

“…The crosstalk between endocytic mechanisms makes it especially challenging to study these mechanisms. Not only can one and the same protein be involved in more than one mechanism; for instance, the small GTP-binding protein cdc42 is involved in the CLIC/GEEC pathway, macropinocytosis, and in FEME (fast endophilin-mediated endocytosis), but there is also a complex crosstalk between the various mechanisms [72,99]. In 2010, Pagano and collaborators reported that there is a coregulation of cdc42-dependent uptake and caveolar endocytosis [104].…”

“…A few years later, not only caveolin but also cavins were published to be involved in such a coregulation [105]. Thus, there has been an incredible development when it comes to our knowledge about endocytic mechanisms [72,99].…”

Molecular mechanism of Fast Endophilin-Mediated Endocytosis

“…Clathrin-mediated endocytosis (hereafter, CME) is the best-characterized and the constitutively active and dominant uptake mechanism to support housekeeping functions in all eukaryotic cells [1][2][3]. There is evidence of several distinct mechanisms of Clathrin-independent endocytosis (CIE), including the CLIC/GEEC pathway (Clathrin-independent carriers (CLIC), glycosylphosphatidylinositol-anchored proteins (GPI-AP)-enriched early endosomal compartments (GEEC)), IL2Rβ uptake, EGFR non-clathrin endocytosis (EGFR-NCE), Fast Endophilin-Mediated Endocytosis (FEME), massive endocytosis (MEND), macropinocytosis, as well as neuron-specific activity-dependent bulk endocytosis (ADBE) and ultrafast endocytosis (UFE) [4][5][6][7][8][9] (Figure 1). Caveolae can in theory contribute to Clathrin-independent uptake.…”

“…Even though caveolae can bud from the cell surface, few if any cargoes rely on them for their uptake [10,11]. The pathways are defined by characteristic endocytic carrier morphologies, by cytosolic markers, by ligands and receptors (collectively called 'cargoes') that use them to enter cells or by the speed of completion [6][7][8][9]12]. Overall, CIE pathways were observed in a wide variety of in vitro cell lines, ex vivo primary cells, as well as in vivo in mouse, fly, worm, plant and yeast.…”