Unconventional secretion mediated by direct protein self-translocation across the plasma membranes of mammalian cells

Unconventional protein secretion (UPS) is a term collectively used for different kinds of endoplasmic reticulum (ER)/Golgi-independent secretory pathways that have been classified into subtypes that are either mediated by direct protein translocation across the plasma membrane (type I and II UPS) or involve vesicular transport intermediates inside cells (type III and IV UPS). A unifying principle of type I UPS cargo proteins such as fibroblast growth factor 2 (FGF2), HIV-Tat, Tau, and EN2 is their ability to directly bind to PI(4,5)P2. FGF2 is a type I UPS cargo protein that can self-translocate across the plasma membrane, a process that depends on PI(4,5)P2-dependent oligomerization at the inner leaflet and heparan sulfates at the outer plasma membrane leaflet. In intact cells, the Na,K-ATPase plays a key role in unconventional secretion of FGF2 being required for the initial recruitment of FGF2 at the inner plasma membrane leaflet. Glypican-1 (GPC1) is a GPI-anchored heparan sulfate proteoglycan that drives unconventional secretion of FGF2 with FGF2 capturing at the outer leaflet being the rate-limiting step of this process. The intimate relationship between GPC1 and FGF2 as part of its type I UPS pathway has important implications for their roles in tumor progression and metastasis. In recent years, a surprisingly complex picture emerged about endoplasmic reticulum (ER)/Golgi-independent secretory pathways, and several routes have been discovered that differ with regard to their molecular mechanisms and machineries. Fibroblast growth factor 2 (FGF2) is secreted by a pathway of unconventional protein secretion (UPS) that is based on direct self-translocation across the plasma membrane. Building on previous research, a component of this process has been identified to be glypican-1 (GPC1), a GPI-anchored heparan sulfate proteoglycan located on cell surfaces. These findings not only shed light on the molecular mechanism underlying this process but also reveal an intimate relationship between FGF2 and GPC1 that might be of critical relevance for the prominent roles they both have in tumor progression and metastasis. In recent years, a surprisingly complex picture emerged about endoplasmic reticulum (ER)/Golgi-independent secretory pathways, and several routes have been discovered that differ with regard to their molecular mechanisms and machineries. Fibroblast growth factor 2 (FGF2) is secreted by a pathway of unconventional protein secretion (UPS) that is based on direct self-translocation across the plasma membrane. Building on previous research, a component of this process has been identified to be glypican-1 (GPC1), a GPI-anchored heparan sulfate proteoglycan located on cell surfaces. These findings not only shed light on the molecular mechanism underlying this process but also reveal an intimate relationship between FGF2 and GPC1 that might be of critical relevance for the prominent roles they both have in tumor progression and metastasis. a concept proposed to explain the role of cell surface heparan sulfates capturing and disassembling plasma membrane-associated FGF2 complexes as the final step of FGF2 secretion ensuring unidirectional transport of FGF2 across the plasma membrane. ternary complexes on cell surfaces consisting of high-affinity FGF receptors, heparan sulfate chains, and FGF2 transmitting mitogenic signals into cells. artificial membrane vesicles with large diameters (≥10 μm) and a single limiting membrane that can be imaged by confocal microscopy. a heparan sulfate proteoglycan that is associated with the plasma membrane via a GPI anchor and contains three O-linked heparan sulfate chains in close proximity to the cell surface. transport phenomena observed for various kinds of integral membrane proteins that are inserted into the ER and get transported to the plasma membrane in a Golgi-independent manner. extended, unbranched chains of O-linked repetitions of disaccharide units made from xylose, galactose, glucuronic acid, N-acetylgalactosamine, iduronic acid as well as sulfated variants of N-acetylgalactosamine and iduronic acid that are contained as post-translational modifications in various kinds of proteoglycans such as glypicans and syndecans. membrane-associated proteins containing at least one membrane-spanning hydrophobic element. membrane pores that are not stabilized by integral membrane proteins but rather are induced by the oligomerization of soluble membrane lipid-binding proteins that trigger the formation of pores with a toroidal architecture. small membrane domains that are enriched in cholesterol and sphingomyelin and are characterized by a physical state in which the lateral mobility of membrane components is limited. pathways of protein secretion from mammalian cells with the secreted proteins not traveling through the lumen of the ER and the Golgi apparatus.