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Apart from the caveolar and CLIC/GEEC clathrin-independent endocytic (CIE) routes, a number of other CIE pathways that operate at smaller scales have been described. These include endocytosis of the IL-2R receptor , Arf6-mediated endocytosis , flotillin-mediated endocytosis  and the recently discovered fast endophilin-mediated endocytosis (FEME) .
Internalization of transmembrane receptors was thought to occur exclusively via clathrin-mediated endocytosis (CME). However, the discovery of clathrin-independent endocytic routes, in particular, the pathway that mediates the internalization of the cytokine receptor interleukin-2 (IL-2R), raises into question the interchangeable use of the term ‘receptor-mediated endocytosis’ as a synonym for CME . It has been proposed that the specific endocytic mechanism is used to describe the pathway.
The endocytosis of the cytokine receptor IL-2R, occurs via a constitutive, clathrin and caveolae-independent, dynamin-dependent route. This pathway is dependent on the Rho small GTPase RhoA  and is regulated by the lipid kinase, phosphoinositide 3-kinase (PI3K) . The current model for IL2-R endocytosis is as follows: 1) IL-2R activates PI3K by interacting with its regulatory p85 subunit, leading to the production of PIP3 at the membrane 2) PIP3 induces Vav2, a guanine nucleotide exchange factor (GEF) for Rac1, that activates Rac1 3) Rac1-GTP directly binds to p85 and thus is recruited to sites containing IL2-R 4) This activates the downstream target of Rac1, the p21-activated kinase1 (Pak1), which phosphorylates cortactin, promoting its association with neuronal Wiskott-Aldrich syndrome proteins (N-WASP), activating actin polymerization. ,   .
Arf6-associated endocytosis is a clathrin-independent, plasma membrane-endosomal recycling pathway, regulated by the Arf6 protein, which is a member of the Arf family of small GTPases . In this pathway, Arf6 cycles between the inactive GDP-bound state and active GTP-bound state. At the plasma membrane Arf6-GTP facilitates internalization of various cargos using energy from GTP hydrolysis, following which, the inactive Arf6-GDP associates with the tubular recycling endosome. Upon further activation by guanine nucleotide exchange factors like Grp1-associated scaffold protein (GRASP) , Arf6-GTP relocates to the plasma membrane and forms protrusive actin-rich structures, recycling membrane back to the cell surface. The Arf6-associated endocytic route requires cholesterol and correspondingly, the Arf6-associated endosomes are rich in cholesterol and PIP2 .
Glycosyl phosphatidylinositol anchor proteins (GPI-APs) like CD55 and CD59, proteins involved in immune function such as MHC Class 1, CD1a, and cell adhesion proteins like cadherins and integrins are some examples of cargo internalized and recycled by this pathway. In fact, Arf6-associated endocytosis is emerging as an important trafficking pathway that regulates cell adhesion, migration, tumor invasion and cytokinesis (reviewed in ). NEDD9, a marker as well as therapeutic target for metastatic breast cancer, inactivates Arf6, blocking the recycling of matrix metalloproteinase 14 (MMP14) back to the cell surface, thus increasing MMP14 activity and facilitating tumor invasion .
FEME is a novel clathrin-independent endocytic pathway, regulated by the BAR domain protein endophilin, where tubulo-vesicular carriers form within seconds at the plasma membrane upon activation of specific G-protein coupled receptors (GPCRs) by their ligands, internalizing GPCRs and moving rapidly towards the perinucleolar area . FEME requires PI3K signaling, where class 1 PI3K, upon receptor activation, phosphorylates phosphatidylinositol-4,5-bisphosphate (PtdIns (4,5)P2 or PIP2), producing PIP3. The rapid dephosphorylation of PIP3 back into PIP2 by the SHIP phosphatases recruits lamellipodin at the leading edge of migrating cells, which subsequently binds endophilin. This accumulation of endophilin induces the FEME pathway . Endophilin alone performs 3 distinct functions in this pathway: its SH3 domain binds to cargo receptors, its BAR domain induces membrane curvature and its multiple membrane helices supports membrane scission in co-operation with dynamin and actin. This pathway is hijacked by bacterial Shiga and cholera toxins for infection, demonstrated by endophilin coating tubule-shaped membrane invaginations that arise when Shiga toxin B binds to the cell membrane .