You will be presented with the abstract, introduction, and discussion section from a biomedical research article. Your task is to create a summary that a layperson can understand, capturing the essence of the research article. Keep essential scientific terms, but ensure that the language remains clear and the concepts are explained in an uncomplicated manner.

Title: A plasma membrane template for macropinocytic cups}
Article:
Abstract:
Macropinocytosis is a fundamental mechanism that allows cells to take up extracellular liquid into large vesicles. It critically depends on the formation of a ring of protrusive actin beneath the plasma membrane, which develops into the macropinocytic cup. We show that macropinocytic cups in Dictyostelium are organised around coincident intense patches of PIP3, active Ras and active Rac. These signalling patches are invariably associated with a ring of active SCAR/WAVE at their periphery, as are all examined structures based on PIP3 patches, including phagocytic cups and basal waves. Patch formation does not depend on the enclosing F-actin ring, and patches become enlarged when the RasGAP NF1 is mutated, showing that Ras plays an instructive role. New macropinocytic cups predominantly form by splitting from existing ones. We propose that cup-shaped plasma membrane structures form from self-organizing patches of active Ras/PIP3, which recruit a ring of actin nucleators to their periphery.
Introduction:
Macropinocytosis provides cells with an efficient way of taking up large volumes of medium into intracellular vesicles, from which they can extract nutrients, antigens and other useful molecules( Bloomfield and Kay, 2016; Egami et al., 2014; Maniak, 2001; Swanson, 2008; Swanson and Watts, 1995). It is an ancient process, used for feeding by amoebae( Hacker et al., 1997; Thilo and Vogel, 1980), but one that is important for a wide spectrum of human biology, including uptake of drugs, and large-scale sampling of extracellular medium for antigens by immune cells. It has also been hijacked by pathogens as a major route of entry( Mercer and Helenius, 2012). Recent data suggest that macropinocytosis is a principal and widely used method for sustaining the excessive metabolic demands of cancer cells( Commisso et al., 2013; Kamphorst et al., 2015) and may be implicated in the spread of neurodegenerative disease within the brain( Münch et al., 2011). Considering its biological importance, macropinocytosis is not well understood. Macropinosomes form from cup-shaped extensions of the plasma membrane, often known as circular ruffles, which are extended by actin polymerisation. The leading rims of these ruffles must be driven outwards to enclose liquid – often for a very significant fraction of the cell’s diameter – but the base must be held static. The resulting cups can be several microns in diameter, and eventually close by constriction of their rim, with membrane fusion producing an endocytic vesicle. Here we address a critical and mysterious question about this process- how do cells organize actin to polymerize in a ring and so form the walls of the cup? In the closely related process of phagocytosis, in which solid particles are taken up, it is proposed that cup formation is guided by engaging receptors with the particle to be engulfed in a zippering process( Freeman and Grinstein, 2014; Griffin et al., 1975). However, macropinosomes take up fluid and so cannot use a particle as a template in this way. Nor is there any known equivalent in macropinocytosis of the coat that organises clathrin-mediated endocytosis. Thus it appears that macropinocytic cups must form by a self-organizing process within the actin polymerization machinery and its regulators. The dynamic actin that polymerises around macropinocytic cups is probably initiated by a number of nucleators, including both formins, such as ForG, which is needed for the basal part of phagocytic cups in Dictyostelium( Junemann et al., 2016), and the Arp2/3 complex( Insall et al., 2001), which produces dendritic structures( Pollard and Borisy, 2003), like the actin that drives pseudopods. Assembly of Arp2/3 based actin is controlled by the WASP family of nucleation promoting factors; the two family members that act at the plasma membrane are WASP and SCAR/WAVE( hereafter called SCAR). WASP is important for actin polymerisation during clathrin-mediated endocytosis( Taylor et al., 2011), and SCAR, acting in a five-membered complex( Eden et al., 2002), for the formation of pseudopods( Seastone et al., 2001; Veltman et al., 2012). It is not known which is responsible for macropinocytosis. Ras and phosphoinositide signalling help organize the cytoskeleton for macropinocytosis and phagocytosis( Bar-Sagi and Feramisco, 1986; Bloomfield and Kay, 2016; Bohdanowicz and Grinstein, 2013; Rodriguez-Viciana et al., 1997; Swanson, 2014). There is evidence that Ras activity stimulates macropinocytosis in both mammalian and Dictyostelium cells, and macropinocytic cups are associated with an intense domain, or ‘patch’, of PIP3( Araki et al., 2007; Parent et al., 1998; Yoshida et al., 2009), which is essential for their function( Araki et al., 1996; Buczynski et al., 1997; Hoeller et al., 2013; Zhou et al., 1998). In macrophages, which often evolve macropinocytic cups from linear ruffles, it has been suggested that ruffle circularisation creates a diffusion barrier in the membrane leading to intensified PIP3 signalling and a domain of PIP3 in the centre of the circular ruffle( Welliver et al., 2011). This domain then drives the further progression of the macropinocytic cup. In axenic strains of Dictyostelium, which grow efficiently in liquid medium, macropinocytosis is massively up-regulated due to mutation of the RasGAP neurofibromatosis-1( NF1)( Bloomfield et al., 2015; Hacker et al., 1997; Kayman and Clarke, 1983). These strains are thus an excellent starting point for research into the organising principles behind macropinocytic cup formation. Here we examine macropinocytosis with unprecedented 3D detail using lattice light sheet microscopy, and map the spatial and temporal control of actin regulators such as SCAR and WASP with respect to signalling molecules including PIP3 and active Ras. This leads us to propose a new and general hypothesis for the formation of cups from the plasma membrane.
Discussion:
Macropinosomes develop from cup-shaped projections of the plasma membrane, whose walls are driven outwards by actin polymerization. They contain a central patch of activated Ras and PIP3 throughout their life and we find that in Dictyostelium, this patch is invariably associated with a ring of active SCAR at its edge. We propose that this ring of active SCAR is recruited by the signalling patch and drives a hollow ring of F-actin to extend the walls of the macropinocytic cup. A possible alternative mechanism comes from immune cells, which make abundant linear ruffles. These occasionally fold back to form circular ruffles, which have been described as diffusion traps that can intensify signalling within them, leading to the formation of a patch of active Ras and PIP3,( Welliver et al., 2011). In this model, PIP3 patches form as a consequence of circular ruffle formation, rather than as a cause of it. Despite the evidence that sharply curved membrane areas such as those present at the leading edge of lamellipods can act as a diffusion barrier( Weisswange et al., 2005), this idea does not easily extend to Dictyostelium, where linear ruffles are much less common, and the central PIP3 patch of macropinocytic cups can still form when ruffle formation is inhibited. However it remains possible that a diffusion barrier forms by a ruffle-independent mechanism, for example by septin-like molecules( Golebiewska et al., 2011), or perhaps by cross-linking components within the patch. Further, Dictyostelium patches become larger when Ras signalling is increased by NF1 inactivation, showing that Ras plays an instructive part in their formation. PIP3 patches are coincident with patches of activated Ras, which presumably support them by activating PI3-kinase, and also of activated Rac. Previous work suggest that patches are self-organising structures, which can form independently of input from G-protein coupled receptors( Sasaki et al., 2007) and are likely dependent on positive feedback loops between their components( Postma et al., 2003, 2004). Our results argue against an essential role for feedback from PIP3 to Ras, because activated Ras patches can form independently of type-1 PI3-kinases and are still able to recruit SCAR to their edges, albeit less efficiently than when PI3-kinases are present. Thus it appears that the kinetics that lead to patch formation must lie largely within the compass of the GEFs and GAPs activating and inactivating Ras. We can only speculate on how SCAR is recruited to the periphery of Ras/PIP3 patches. One possibility is that SCAR and Arp2/3 are preferentially recruited by newly synthesised F-actin( Ichetovkin et al., 2002) produced by formins( Jasnin et al., 2016), which might therefore be the initial actin nucleator to be recruited. However, this seems unlikely in the light of recent work showing that ForG contributes to the base of the macropinocytic cup, but seemingly not to the extending lip( Junemann et al., 2016). Alternatively, SCAR might be moved to the periphery of Ras/PIP3 patches, perhaps by myosin-1 motors. Early work showed that myosin-1 is genetically important for macropinocytosis in Dictyostelium( Novak et al., 1995; Titus, 2000). In support of the genetic evidence, myosin-1 isoforms are recruited to macropinocytic cups in both Dictyostelium and Acanthamoeba( Brzeska et al., 2012; Ostap et al., 2003), most likely due to their affinity for PIP3( Chen et al., 2012). The PIP3-binding MyoE and MyoF are recruited in the centre and MyoB at the periphery of macropinocytic cups, forming a striking ‘bull’s eye’ pattern( Brzeska et al., 2016; Dieckmann et al., 2010). In such a scenario, CARMIL may provide the link between myosin-1 and SCAR( Jung et al., 2001). Our work also has implications more specific to Dictyostelium biology. First, the basal actin waves, which give a valuable window into actin dynamics( Bretschneider et al., 2004, 2009; Gerisch, 2010), appear to be formed as a consequence of the loss of NF1 in standard laboratory axenic strains. Knowing this should allow for better manipulation of these waves and for modelling to take account of their underlying need for activated Ras( Arai et al., 2010; Khamviwath et al., 2013; Sasaki et al., 2007; Taniguchi et al., 2013). Second, we consider that all patches of PIP3 and activated Ras are related by their common recruitment of SCAR to their periphery and are therefore likely to organise circular rings of actin polymerization, rather than the solid blocks characteristic of pseudopods. Therefore, the proposed role of these patches in chemotaxis, where they have been mistaken for pseudopods, needs to be re-evaluated. In summary, our work suggests a general hypothesis for the formation of cupped actin structures: that these structures arise from a ring of actin polymerization formed by recruiting actin nucleators to the periphery, but not the centre, of self-organizing patches of intense Ras and PIP3 signalling. This hypothesis suggests many new lines of experimentation.
Cells can use a process known as macropinocytosis to take up fluid from their surroundings . This process plays an important role in many situations . For example , it allows human immune cells to sample their environment to search for harmful microbes and viruses and helps cancer cells to collect more nutrients so that they can grow more rapidly . During macropinocytosis , a protein called actin – which provides structural support to cells – drives the formation of cup-shaped structures from the membrane that surrounds the cell . Several signaling molecules control when and where the “cups” form , but it was not known exactly how the different types of molecules work together . Here Veltman et al . used a technique called lattice light sheet microscopy to investigate how the macropinocytic cups form in a single-celled amoeba known as Dictyostelium . The experiments revealed that to make a cup , the actin first arranges to form a ring . The ring copies a template in the membrane , which consists of high concentrations of signaling molecules , and then extends outward to form a hollow cup by which fluid is taken up . The most important signaling molecule identified in these patches of membrane is a protein called Ras , which is mutated and hyperactive in many different types of cancer . In Dictyostelium cells that have a genetic mutation that makes Ras more active , the patches of signaling molecules and macropinocytic cups were larger than in normal cells . The findings of Veltman et al . provide new details about how cells engulf fluids from their surroundings . The next steps will be to investigate how the signaling molecules form patches in the first place , and how they attract actin molecules . Also , more research is necessary to find out whether all cells take up fluid in a similar way or if other methods have evolved in mammalian cells .