Cadherin Binding Research Articles

Cadherin-dependent mechanotransduction depends on ligand identity but not affinity

This study investigates the relationship between classical cadherin binding affinities and mechanotransduction through cadherin-mediated adhesions. The mechanical properties of cadherin-dependent intercellular junctions are generally attributed to differences in the binding affinities of classical cadherin subtypes that contribute to cohesive energies between cells. However, cell mechanics and mechanotransduction may also regulate intercellular contacts. We used micropipette measurements to quantify the two-dimensional affinities of cadherins at the cell surface, and two complementary mechanical measurements to assess ligand-dependent mechanotransduction through cadherin adhesions. At the cell surface, the classical cadherins investigated in this study form both homophilic and heterophilic bonds with two-dimensional affinities that differ by less than threefold. In contrast, mechanotransduction through cadherin adhesions is strongly ligand dependent such that homophilic, but not heterophilic ligation mediates mechanotransduction, independent of the cadherin binding affinity. These findings suggest that ligand-selective mechanotransduction may supersede differences in cadherin binding affinities in regulating intercellular contacts.

Adhesion Frequency Assay for <em>In Situ</em> Kinetics Analysis of Cross-Junctional Molecular Interactions at the Cell-Cell Interface

The micropipette adhesion assay was developed in 1998 to measure two-dimensional (2D) receptor-ligand binding kinetics. The assay uses a human red blood cell (RBC) as adhesion sensor and presenting cell for one of the interacting molecules. It employs micromanipulation to bring the RBC into contact with another cell that expresses the other interacting molecule with precisely controlled area and time to enable bond formation. The adhesion event is detected as RBC elongation upon pulling the two cells apart. By controlling the density of the ligands immobilized on the RBC surface, the probability of adhesion is kept in mid-range between 0 and 1. The adhesion probability is estimated from the frequency of adhesion events in a sequence of repeated contact cycles between the two cells for a given contact time. Varying the contact time generates a binding curve. Fitting a probabilistic model for receptor-ligand reaction kinetics to the binding curve returns the 2D affinity and off-rate. The assay has been validated using interactions of Fcγ receptors with IgG Fc, selectins with glycoconjugate ligands, integrins with ligands, homotypical cadherin binding, T cell receptor and coreceptor with peptide-major histocompatibility complexes. The method has been used to quantify regulations of 2D kinetics by biophysical factors, such as the membrane microtopology, membrane anchor, molecular orientation and length, carrier stiffness, curvature, and impingement force, as well as biochemical factors, such as modulators of the cytoskeleton and membrane microenvironment where the interacting molecules reside and the surface organization of these molecules. The method has also been used to study the concurrent binding of dual receptor-ligand species, and trimolecular interactions using a modified model. The major advantage of the method is that it allows study of receptors in their native membrane environment. The results could be very different from those obtained using purified receptors. It also allows study of the receptor-ligand interactions in a sub-second timescale with temporal resolution well beyond the typical biochemical methods. To illustrate the micropipette adhesion frequency method, we show kinetics measurement of intercellular adhesion molecule 1 (ICAM-1) functionalized on RBCs binding to integrin α(L)β(2) on neutrophils with dimeric E-selectin in the solution to activate α(L)β(2).

N-cadherin–mediated cell adhesion restricts cell proliferation in the dorsal neural tube

Neural progenitors are organized as a pseudostratified epithelium held together by adherens junctions (AJs), multiprotein complexes composed of cadherins and α- and β-catenin. Catenins are known to control neural progenitor division; however, it is not known whether they function in this capacity as cadherin binding partners, as there is little evidence that cadherins themselves regulate neural proliferation. We show here that zebrafish N-cadherin (N-cad) restricts cell proliferation in the dorsal region of the neural tube by regulating cell-cycle length. We further reveal that N-cad couples cell-cycle exit and differentiation, as a fraction of neurons are mitotic in N-cad mutants. Enhanced proliferation in N-cad mutants is mediated by ligand-independent activation of Hedgehog (Hh) signaling, possibly caused by defective ciliogenesis. Furthermore, depletion of Hh signaling results in the loss of junctional markers. We therefore propose that N-cad restricts the response of dorsal neural progenitors to Hh and that Hh signaling limits the range of its own activity by promoting AJ assembly. Taken together, these observations emphasize a key role for N-cad-mediated adhesion in controlling neural progenitor proliferation. In addition, these findings are the first to demonstrate a requirement for cadherins in synchronizing cell-cycle exit and differentiation and a reciprocal interaction between AJs and Hh signaling.

Resolving Desmosomal Cadherin Interactions at the Single Molecule Level

Desmocollin and Desmoglein are essential Ca2+ dependent cell adhesion proteins that mediate the integrity and functional organization of tissues in multi-cellular organisms; however, the molecular interactions that mediate their binding are not understood. It is currently believed that desmosomal cadherin cis-dimers are required to mediate adhesion, evidence for the role of cis-dimers is lacking. Furthermore, it is unclear if desmosomal cadherins interact via homophilic or heterophilic binding and the molecular mechanism by which desmosomal cadherins enhance their bond-strength. To resolve these questions we used Dynamic Force Spectroscopy with an Atomic Force Microscope to measure the homophilic and heterophilic binding of desmosomal cadherin monomers and cis-dimers at the single molecule level. Our measurements showed that desmosomal cadherin monomers alone mediate Ca2+ dependent adhesion, cis-dimers are not essential for adhesion. Furthermore, while desmocollin and desmoglein participate in Ca2+ dependent heterophilic binding, we could not measure Ca2+ dependent homophilic interactions between these cadherins. Dynamic Force Spectroscopy revealed that desmosomal cadherin interactions occur via a double barrier interaction potential; at low loading rates the outer barrier serves as the dominant impedance to unbinding while at higher loading rates the inner barrier serves as the primary kinetic barrier. These experiments resolve the molecular details of desmosomal cadherin binding and suggest a mechanism by which these essential cell adhesion molecules enhance bond strength and lifetime in the presence of force.

Membrane-impermeable Cross-linking Provides Evidence for Homophilic, Isoform-specific Binding of Desmosomal Cadherins in Epithelial Cells

Desmosomes and adherens junctions are cadherin-based protein complexes responsible for cell-cell adhesion of epithelial cells. Type 1 cadherins of adherens junctions show specific homophilic adhesion that plays a major role in developmental tissue segregation. The desmosomal cadherins, desmocollin and desmoglein, occur as several different isoforms with overlapping expression in some tissues where different isoforms are located in the same desmosomes. Although adhesive binding of desmosomal cadherins has been investigated in a variety of ways, their interaction in desmosome-forming epithelial cells has not been studied. Here, using extracellular homobifunctional cross-linking, we provide evidence for homophilic and isoform-specific binding between the Dsc2, Dsc3, Dsg2, and Dsg3 isoforms in HaCaT keratinocytes and show that it represents trans interaction. Furthermore, the cross-linked adducts are present in the detergent-insoluble fraction, and electron microscopy shows that extracellular cross-linking probably occurs in desmosomes. We found no evidence for either heterophilic or cis interaction, but neither can be completely excluded by our data. Mutation of amino acid residues Trp-2 and Ala-80 that are important for trans interaction in classical cadherin adhesive binding abolished Dsc2 binding, indicating that these residues are also involved in desmosomal adhesion. These interactions of desmosomal cadherins may be of key importance for their ordered arrangement within desmosomes that we believe is essential for desmosomal adhesive strength and the maintenance of tissue integrity.

Cooperativity between trans and cis interactions in cadherin-mediated junction formation

Intercellullar junctions formed by cadherins, including desmosomes and adherens junctions, comprise two dimensional arrays of "trans" dimers formed between monomers emanating from opposing cell surfaces. Lateral "cis" interfaces between cadherins from the same cell surface have been proposed to play a role in cadherin clustering. Although the molecular details of cis interactions remain uncertain, they must define an anisotropic arrangement where binding is favorable only in certain orientations. Here we report Monte Carlo simulations performed on a 2D lattice constructed to account for the anisotropy in cadherin cis interactions. A crucial finding is that the "phase transition" between freely diffusing cadherin monomers and dimers and a condensed ordered 2D junction formed by dimers alone is a cooperative process involving both trans and cis interactions. Moreover, cis interactions, despite being too weak to be measured in solution, are critical to the formation of an ordered junction structure. We discuss these results in light of available experimental information on cadherin binding free energies that are transformed from their bulk solution values to interaction energies on a 2D lattice.

β-Catenin Phosphorylated at Serine 45 Is Spatially Uncoupled from β-Catenin Phosphorylated in the GSK3 Domain: Implications for Signaling

C. elegans and Drosophila generate distinct signaling and adhesive forms of β-catenin at the level of gene expression. Whether vertebrates, which rely on a single β-catenin gene, generate unique adhesive and signaling forms at the level of protein modification remains unresolved. We show that β-catenin unphosphorylated at serine 37 (S37) and threonine 41 (T41), commonly referred to as transcriptionally Active β-Catenin (ABC), is a minor nuclear-enriched monomeric form of β-catenin in SW480 cells, which express low levels of E-cadherin. Despite earlier indications, the superior signaling activity of ABC is not due to reduced cadherin binding, as ABC is readily incorporated into cadherin contacts in E-cadherin-restored cells. β-catenin phosphorylated at serine 45 (S45) or threonine 41 (T41) (T41/S45) or along the GSK3 regulatory cassette S33, S37 or T41 (S33/37/T41), however, is largely unable to associate with cadherins. β-catenin phosphorylated at T41/S45 and unphosphorylated at S37 and T41 is predominantly nuclear, while β-catenin phosphorylated at S33/37/T41 is mostly cytoplasmic, suggesting that β-catenin hypophosphorylated at S37 and T41 may be more active in transcription due to its enhanced nuclear accumulation. Evidence that phosphorylation at T41/S45 can be spatially separated from phosphorylations at S33/37/T41 suggests that these phosphorylations may not always be coupled, raising the possibility that phosphorylation at S45 serves a distinct nuclear function.

Using a mathematical model of cadherin-based adhesion to understand the function of the actin cytoskeleton

The actin cytoskeleton plays a role in cell-cell adhesion but its specific function is not clear. Actin might anchor cadherins or drive membrane protrusions in order to facilitate cell-cell adhesion. Using a mathematical model of the forces involved in cadherin-based adhesion, we investigate its possible functions. The immersed boundary method is used to model the cell membrane and cortex with cadherin binding forces added as linear springs. The simulations indicate that cells in suspension can develop normal cell-cell contacts without actin-based cadherin anchoring or membrane protrusions. The cadherins can be fixed in the membrane or free to move, and the end results are similar. For adherent cells, simulations suggest that the actin cytoskeleton must play an active role for the cells to establish cell-cell contact regions similar to those observed in vitro.

Bridging Cadherin-mediated Cell Adhesion to Multicellular Pattern Formation by Multiscale Modeling and Simulation

The difficulty to study the cadherin-mediated cell adhesion lies in the complexity from cadherin binding specificity to multi-cellular pattern formation. Cadherins are the main adhesion molecules on the cell membrane to hold cells together. They play important roles in many biological processes, such as cell sorting during embryonic development, acting as tumor-suppressors and also mediating cell signaling. Cadherin binding specificities have been shown to be primarily homophilic, but can be more promiscuous. On the other hand, cell-cell adhesion specificity is not simply correlated with molecular-binding specificity within the cadherin family. It has been suggested that cellular binding specificity also arises from differences in overall cadherin cell surface concentration. In order to understand how these different factors lead to various multi-cellular pattern formation results, we present a computational strategy to model the relation between cadherin binding and cell adhesion in multi-scale. Three levels of simulation schemes in different resolutions are constructed to model the multiple cellular system, cell membrane interface and cadherin molecular binding, respectively. Results generated from higher level of simulation are used as input parameters for the simulation in lower level, which combine different modeling into a comprehensive and hierarchic computational strategy. Results from different experimental methods can further be used to guide or parameterize our modeling, and also can be used to compare with our simulation results. Current simulation results show that different adhesion energetic parameters can lead to different multi-cellular patterns, consistent with the experimental data. Future improvements and potential applications are also discussed.

Resolving Cadherin Interactions at the Single Molecule Level

The cadherin family of Calcium-dependent cell adhesion proteins are critical for the morphogenesis and functional organization of tissues in multicellular organisms, but the molecular interactions that are at the core of cadherin binding are poorly understood. The generally accepted model is that cadherins adhere in three stages. First, the functional unit of cadherin adhesion is a cis-dimer formed by the binding of the extracellular regions of two cadherins on the same cell surface. Second, formation of low affinity trans interactions between cadherin cis-dimers on opposing cell surfaces initiates cell-cell adhesion, and third lateral clustering of cadherins cooperatively strengthens intercellular adhesion. Direct molecular proof of these cadherin binding states during adhesion is, however, contradictory, and evidence for cooperativity is lacking. We used single molecule structural (Fluorescence Resonance Energy Transfer) and functional (Atomic Force Microscopy) assays to demonstrate directly that cadherin monomers interact via their outermost domain to form trans adhesive complexes. We could not detect the formation of cadherin cis-dimers, but found that increasing the density of cadherin monomers cooperatively increased the probability of trans-adhesive binding. We also resolved the role of Tryptophan-2 a key amino acid in cadherin trans-binding. These results resolve conflicting data on trans- and cis-cadherin binding states, and provide quantitative evidence for cooperativity in trans-cadherin adhesion.

Resolving cadherin interactions and binding cooperativity at the single-molecule level

The cadherin family of Ca(2+)-dependent cell adhesion proteins are critical for the morphogenesis and functional organization of tissues in multicellular organisms, but the molecular interactions between cadherins that are at the core of cell-cell adhesion are a matter of considerable debate. A widely-accepted model is that cadherins adhere in 3 stages. First, the functional unit of cadherin adhesion is a cis dimer formed by the binding of the extracellular regions of 2 cadherins on the same cell surface. Second, formation of low-affinity trans interactions between cadherin cis dimers on opposing cell surfaces initiates cell-cell adhesion. Third, lateral clustering of cadherins cooperatively strengthens intercellular adhesion. Evidence of these cadherin binding states during adhesion is, however, contradictory, and evidence for cooperativity is lacking. We used single-molecule structural (fluorescence resonance energy transfer) and functional (atomic force microscopy) assays to demonstrate directly that cadherin monomers interact via their N-terminal EC1 domain to form trans adhesive complexes. We could not detect the formation of cadherin cis dimers, but found that increasing the density of cadherin monomers cooperatively increased the probability of trans adhesive binding.

P120 Catenin Recruits Cadherins to γ-Secretase and Inhibits Production of Aβ Peptide

The gamma-secretase complex cleaves many transmembrane proteins, including amyloid precursor protein, EphB and ErbB tyrosine kinase receptors, Notch1 receptors, and adhesion factors. Presenilin 1, the catalytic subunit of gamma-secretase, associates with the cadherin/catenin cell-cell adhesion/communication system and promotes cadherin processing (Georgakopoulos, A., et al. (1999) Mol. Cell 4, 893-902; Marambaud, P., et al. (2002) EMBO J. 21, 1948-1956), but the mechanism by which gamma-secretase and cadherins associate is unclear. Here we report that p120 catenin (p120ctn), a component of the cadherin-catenin complex, recruits gamma-secretase to cadherins, thus stimulating their processing while inhibiting production of Abeta peptide and the amyloid precursor protein intracellular domain. This function of p120ctn depends on both p120ctn-cadherin and p120ctn-presenilin 1 binding, indicating that p120ctn is the central factor that bridges gamma-secretase and cadherin-catenin complexes. Our data show that p120ctn is a unique positive regulator of the gamma-secretase processing of cadherins and a negative regulator of the amyloid precursor protein processing. Furthermore, our data suggest that specific members of the gamma-secretase complex may be used to recruit different substrates and that distinct PS1 sequences are required for processing of APP and cadherins.

From Single Molecules to Living Cells: Nanomechanical Measurements of Cell Adhesion

This review highlights complementary force probe techniques and illustrates how these approaches provide different, but complementary insight into molecular mechanisms of cell adhesion. As a model system, we focus on classical cadherins, which mediate cell–cell adhesion in all solid tissues. The experimental approaches described probe cadherin binding from single molecules to cells, and quantify the kinetics, energetics, and mechanical strengths of cadherin-mediated adhesive contacts. The cumulative findings of these complementary studies reveal complexities of the cadherin binding mechanism, and quantify relevant bond parameters. Importantly these different approaches demonstrate how the strengths and kinetics of cadherin bonds at the single molecule level govern the initial dynamics of adhesion between living cells. The findings also exemplify the capacity of these different force probe techniques to identify novel properties of molecular interactions governing biological adhesion.

A δ-Catenin Signaling Pathway Leading to Dendritic Protrusions

Delta-catenin is a synaptic adherens junction protein pivotally positioned to serve as a signaling sensor and integrator. Expression of delta-catenin induces filopodia-like protrusions in neurons. Here we show that the small GTPases of the Rho family act coordinately as downstream effectors of delta-catenin. A dominant negative Rac prevented delta-catenin-induced protrusions, and Cdc42 activity was dramatically increased by delta-catenin expression. A kinase dead LIMK (LIM kinase) and a mutant Cofilin also prevented delta-catenin-induced protrusions. To link the effects of delta-catenin to a physiological pathway, we noted that (S)-3,5-dihydroxyphenylglycine (DHPG) activation of metabotropic glutamate receptors induced dendritic protrusions that are very similar to those induced by delta-catenin. Furthermore, delta-catenin RNA-mediated interference can block the induction of dendritic protrusions by DHPG. Interestingly, DHPG dissociated PSD-95 and N-cadherin from the delta-catenin complex, increased the association of delta-catenin with Cortactin, and induced the phosphorylation of delta-catenin within the sites that bind to these protein partners.

Biophysical Properties of Cadherin Bonds Do Not Predict Cell Sorting

Differential binding between cadherin subtypes is widely believed to mediate cell sorting during embryogenesis. However, a fundamental unanswered question is whether cell sorting is dictated by the biophysical properties of cadherin bonds, or by broader, cadherin-dependent differences in intercellular adhesion or membrane tension. This report describes atomic force microscope measurements of the strengths and dissociation rates of homophilic and heterophilic cadherin (CAD) bonds. Measurements conducted with chicken N-CAD, canine E-CAD, and Xenopus C-CAD demonstrated that all three cadherins cross-react and form multiple, intermolecular bonds. The mechanical and kinetic properties of the heterophilic bonds are similar to the homophilic interactions. The thus quantified bond parameters, together with previously reported adhesion energies were further compared with in vitro cell aggregation and sorting assays, which are thought to mimic in vivo cell sorting. Trends in quantified biophysical properties of the different cadherin bonds do not correlate with sorting outcomes. These results suggest that cell sorting in vivo and in vitro is not governed solely by biophysical differences between cadherin subtypes.

Epithelium: sticking it out, together

some cells live within a community of neighboring cells, restricted in time and space, most prominently interacting with cells of similar functions. Some cells live within fixed positions, surrounded on all sides by a loose forest of matrix proteins. Some cells live as nomads, wandering throughout

Simple forces, complex shapes

Form follows physics in the fly eye, say Sascha Hilgenfeldt, Sinem Erisken, and Richard Carthew (Northwestern University, Evanston, IL). Figure 1 Shapes predicted by energy minimization modeling (red lines) match the outlines of cells in the fly eye. The idea that a small set of physical forces governs the shape of tissues goes back at least a hundred years, but there has been little evidence to support it. Now, Hilgenfeldt et al. show that just two parameters—cell elasticity and adhesion strength—can account for the arrangement of cells in the ommatidium, the 20-cell subunit of the fly's compound eye. The geometry of the cone cells in the center of the ommatidium resembles groups of soap bubbles, says Hilgenfeldt, who studies the physics of bubbles, foams, and other “soft solids.” This arrangement suggested that, as in bubble aggregates, adhesion and elasticity might help determine shape. And like bubbles, the cells might be minimizing the surface energy at their interface. To test this theory, the authors created a computer-simulated model of ommatidium geometry. Adhesion in these structures is supplied by cadherins at the cells' apicolateral surfaces. The elasticity of the cell membrane arises from a number of complex interactions between the lipid bilayer and the cytoskeleton but can be characterized by its resistance to deformation. The team found that beginning with cells of random shapes, and then adjusting the relative strengths of cadherin binding and membrane elasticity to minimize the total surface energy of all the cells, they could precisely reproduce the observed geometries of the eye. The model also predicted the abnormal cellular arrangements that are found in various cadherin mutants. “Even a small variation in adhesion can alter cell packing dramatically,” Carthew says. Can other tissue geometries be explained as simply? “We think these results stand as an example for less-ordered epithelia,” Carthew says, though some element of random variation may be needed in the mix to account for these structures. They also hope to model developmental changes with the same principles. “You could imagine that tissues undergoing morphogenesis go through a series of minimal energetic states, dictated by changes in a few factors that regulate cell interactions,” Carthew says, such as placement and number of adhesion molecules or cytoskeletal alterations. Reference: Hilgenfeldt, S., et al. 2008. Proc. Natl. Acad. Sci. USA. 10.1073/pnas.0711077105 [PubMed] [Cross Ref]

Two Stage Cadherin Kinetics Require Multiple Extracellular Domains but Not the Cytoplasmic Region

Micropipette manipulation measurements quantified the pre-steady state binding kinetics between cell pairs mediated by Xenopus cleavage stage cadherin. The time-dependence of the intercellular binding probability exhibits a fast forming, low probability binding state, which transitions to a slower forming, high probability state. The biphasic kinetics are independent of the cytoplasmic region, but the transition to the high probability state requires the third extracellular domain EC3. Deleting either EC3 or EC3-5, or substituting Trp(2) for Ala reduces the binding curves to a simple, monophasic rise in binding probability to a limiting plateau, as predicted for a single site binding mechanism. The two stage cadherin binding process reported here directly parallels previous biophysical studies, and confirms that the cadherin ectodomain governs the initial intercellular adhesion dynamics.

Cadherin‐8 and N‐cadherin differentially regulate pre‐ and postsynaptic development of the hippocampal mossy fiber pathway

Cells sort into regions and groups in part by their selective surface expression of particular classic cadherins during development. In the nervous system, cadherin-based sorting can define axon tracts, restrict axonal and dendritic arbors to particular regions or layers, and may encode certain aspects of synapse specificity. The underlying model has been that afferents and their targets hold in common the expression of a particular cadherin, thereby providing a recognition code of homophilic cadherin binding. However, most neurons express multiple cadherins, and it is not clear whether multiple cadherins all act similarly in shaping neural circuitry. Here we asked how two such cadherins, cadherin-8 and N-cadherin, influence the guidance and differentiation of hippocampal mossy fibers. Using organotypic hippocampal cultures, we find that cadherin-8 regulates mossy fiber fasciculation and targeting, but has little effect on CA3 dendrites. In contrast, N-cadherin regulates mossy fiber fasciculation, but has little impact on axonal growth and targeting. However, N-cadherin is essential for CA3 dendrite arborization. Both cadherins are required for formation of proper numbers of presynaptic terminals. Mechanistically, such differential actions of these two cadherins could, in theory, reflect coupling to distinct intracellular binding partners. However, we find that both cadherins bind beta-catenin in dentate gyrus (DG). This suggests that cadherins may engage different intracellular signaling cascades downstream of beta-catenin, coopt different extracellular binding partners, or target distinct subcellular domains. Together our findings demonstrate that cadherin-8 and N-cadherin are critical for generating the mossy fiber pathway, but that each contributes differentially to afferent and target differentiation, thereby complementing one another in the assembly of a synaptic circuit.

Als3 Is a Candida albicans Invasin That Binds to Cadherins and Induces Endocytosis by Host Cells

Candida albicans is the most common cause of hematogenously disseminated and oropharyngeal candidiasis. Both of these diseases are characterized by fungal invasion of host cells. Previously, we have found that C. albicans hyphae invade endothelial cells and oral epithelial cells in vitro by inducing their own endocytosis. Therefore, we set out to identify the fungal surface protein and host cell receptors that mediate this process. We found that the C. albicans Als3 is required for the organism to be endocytosed by human umbilical vein endothelial cells and two different human oral epithelial lines. Affinity purification experiments with wild-type and an als3Δ/als3Δ mutant strain of C. albicans demonstrated that Als3 was required for C. albicans to bind to multiple host cell surface proteins, including N-cadherin on endothelial cells and E-cadherin on oral epithelial cells. Furthermore, latex beads coated with the recombinant N-terminal portion of Als3 were endocytosed by Chinese hamster ovary cells expressing human N-cadherin or E-cadherin, whereas control beads coated with bovine serum albumin were not. Molecular modeling of the interactions of the N-terminal region of Als3 with the ectodomains of N-cadherin and E-cadherin indicated that the binding parameters of Als3 to either cadherin are similar to those of cadherin–cadherin binding. Therefore, Als3 is a fungal invasin that mimics host cell cadherins and induces endocytosis by binding to N-cadherin on endothelial cells and E-cadherin on oral epithelial cells. These results uncover the first known fungal invasin and provide evidence that C. albicans Als3 is a molecular mimic of human cadherins.