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At least 199 records · Page 11Linked to original sources
PubMed2002

Substitution in the murine nectin1 receptor of a single conserved amino acid at a position distal from the herpes simplex virus gD binding site confers high-affinity binding to gD.

By analogy with its human nectin1 counterpart, murine nectin1 serves as a cellular receptor for the entry of herpes simplex virus (HSV) into murine cells. HSV entry mediated by either receptor is dependent on the viral glycoprotein D (gD). Whereas human nectin1 binds gD at high affinity and in a saturable manner, murine nectin1 binds gD in a barely detectable fashion, depending on the sensitivity of the assay. The immunoglobulin type V domain of murine nectin differs from its human counterpart in 11 amino acids. To identify the key residues responsible for the high-affinity binding of gD to human nectin1, we replaced each of the 11 divergent amino acids with the human counterparts singly or in groups in an incremental manner. Replacement in murine nectin1 of six amino acids that lie within the gD binding region of human nectin1 (previously mapped to residues 64 to 94, likely the CC'C" surface) increased the gD binding activity to a limited extent. In contrast, the single P138L substitution, which lies distal from the gD binding site, markedly increased gD binding. This substitution, when coupled with downstream substitutions, exerted the greatest effect. Three-dimensional modeling of the nectin1 V domain suggested that P138 in murine nectin1 might decrease the stability of the V domain by reducing the size of beta-strand G. The results support the notion that the overall structure of V nectin1 plays a pivotal role in its ability to bind HSV gD.

Amino Acid Sequence↗
PubMed2003

Structure-function analysis of herpes simplex virus type 1 gD and gH-gL: clues from gDgH chimeras.

In alphaherpesviruses, glycoprotein B (gB), gD, gH, and gL are essential for virus entry. A replication-competent gL-null pseudorabies virus (PrV) (B. G. Klupp and T. C. Mettenleiter, J. Virol. 73:3014-3022, 1999) was shown to express a gDgH hybrid protein that could replace gD, gH, and gL in cell-cell fusion and null virus complementation assays. To study this phenomenon in herpes simplex virus type 1 (HSV-1), we constructed four gDgH chimeras, joining the first 308 gD amino acids to various gH N-terminal truncations. The chimeras were named for the first amino acid of gH at which each was truncated: 22, 259, 388, and 432. All chimeras were immunoprecipitated with both gD and gH antibodies to conformational epitopes. Normally, transport of gH to the cell surface requires gH-gL complex formation. Chimera 22 contains full-length gH fused to gD308. Unlike PrV gDgH, chimera 22 required gL for transport to the surface of transfected Vero cells. Interestingly, although chimera 259 failed to reach the cell surface, chimeras 388 and 432 exhibited gL-independent transport. To examine gD and gH domain function, each chimera was tested in cell-cell fusion and null virus complementation assays. Unlike PrV gDgH, none of the HSV-1 chimeras substituted for gL for fusion. Only chimera 22 was able to replace gH for fusion and could also replace either gH or gD in the complementation assay. Surprisingly, this chimera performed very poorly as a substitute for gD in the fusion assay despite its ability to complement gD-null virus and bind HSV entry receptors (HveA and nectin-1). Chimeras 388 and 432, which contain the same portion of gD as that in chimera 22, substituted for gD for fusion at 25 to 50% of wild-type levels. However, these chimeras functioned poorly in gD-null virus complementation assays. The results highlight the fact that these two functional assays are measuring two related but distinct processes.

Animals↗
PubMed2006

Multidirectional interactions are bridging human NK cells with plasmacytoid and monocyte-derived dendritic cells during innate immune responses.

During innate immune responses, natural killer (NK) cells may interact with both plasmacytoid dendritic cells (pDCs) and monocyte-derived dendritic cells (MDDCs). We show that freshly isolated NK cells promote the release by pDCs of IFN-alpha, in a CpG-dependent manner, whereas they induce IL-6 production in a CpG-independent manner. In turn pDC-derived IFN-alpha up-regulates NK-mediated killing, whereas IL-6 could promote B-cell differentiation. We also show that exposure to exogenous IL-12 or coculture with maturing MDDCs up-regulates the NK-cell-dependent IFN-alpha production by pDCs. On the other hand, NK cells cocultured with pDCs acquire the ability to kill immature MDDCs, thus favoring their editing process. Finally, we show that activated NK cells are unable to lyse pDCs because these cells display an intrinsic resistance to lysis. The exposure of pDCs to IL-3 increased their susceptibility to NK-cell cytotoxicity resulting from a de novo expression of ligands for activating NK-cell receptors, such as the DNAM-1 ligand nectin-2. Thus, different cell-to-cell interactions and various cytokines appear to control a multidirectional network between NK cells, MDDCs, and pDCs that is likely to play an important role during the early phase of innate immune responses to viral infections and to tumors.

Antigens, Differentiation, T-Lymphocyte↗
PubMed2004

Contribution of JAM-1 to epithelial differentiation and tight-junction biogenesis in the mouse preimplantation embryo.

We have investigated the contribution of the tight junction (TJ) transmembrane protein junction-adhesion-molecule 1 (JAM-1) to trophectoderm epithelial differentiation in the mouse embryo. JAM-1-encoding mRNA is expressed early from the embryonic genome and is detectable as protein from the eight-cell stage. Immunofluorescence confocal analysis of staged embryos and synchronized cell clusters revealed JAM-1 recruitment to cell contact sites occurred predominantly during the first hour after division to the eight-cell stage, earlier than any other TJ protein analysed to date in this model and before E-cadherin adhesion and cell polarization. During embryo compaction later in the fourth cell cycle, JAM-1 localized transiently yet precisely to the apical microvillous pole, where protein kinase Czeta (PKCzeta) and PKCdelta are also found, indicating a role in cell surface reorganization and polarization. Subsequently, in morulae and blastocysts, JAM-1 is distributed ubiquitously at cell contact sites within the embryo but is concentrated within the trophectoderm apicolateral junctional complex, a pattern resembling that of E-cadherin and nectin-2. However, treatment of embryos with anti-JAM-1-neutralizing antibodies indicated that JAM-1 did not contribute to global embryo compaction and adhesion but rather regulated the timing of blastocoel cavity formation dependent upon establishment of the trophectoderm TJ paracellular seal.

Adherens Junctions↗
PubMed2006

Dynamin II interacts with the cadherin- and occludin-based protein complexes at the blood-testis barrier in adult rat testes.

In adult rat testes, blood-testis barrier (BTB) restructuring facilitates the migration of preleptotene spermatocytes from the basal to the adluminal compartment that occurs at stage VIII of the epithelial cycle. Structural proteins at the BTB must utilize an efficient mechanism (e.g. endocytosis) to facilitate its transient 'opening'. Dynamin II, a large GTPase known to be involved in endocytosis, was shown to be a product of Sertoli and germ cells in the testis. It was also localized to the BTB, as well as the apical ectoplasmic specialization (apical ES), during virtually all stages of the epithelial cycle. By co-immunoprecipitation, dynamin II was shown to associate with occludin, N-cadherin, zonula occludens-1 (ZO-1), beta-catenin, junctional adhesion molecule-A, and p130Cas, but not nectin-3. An in vivo model in rats previously characterized for studying adherens junction (AJ) dynamics in the testes by adjudin (formerly called AF-2364, 1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide) treatment was used in our studies. At the time of germ cell loss from the seminiferous epithelium as a result of adjudin-induced AJ restructuring without disrupting the BTB integrity, a significant decline in the steady-state dynamin II protein level was detected. This change was associated with a concomitant increase in the levels of two protein complexes at the BTB, namely occludin/ZO-1 and N-cadherin/beta-catenin. Interestingly, these changes were also accompanied by a significant increase in the structural interaction of dynamin II with beta-catenin and ZO-1. Beta-catenin and ZO-1 are adaptors that structurally link the cadherin- and occludin-based protein complexes together at the BTB in an 'engaged'state to reinforce the barrier function in normal testes. However, beta-catenin and ZO-1 were 'disengaged' from each other but bound to dynamin II during adjudin-induced AJ restructuring in the testis. The data reported herein suggest that dynamin II may assist the 'disengagement' of beta-catenin from ZO-1 during BTB restructuring. Thus, this may permit the occludin/ZO-1 complexes to maintain the BTB integrity when the cadherin/catenin complexes are dissociated to facilitate germ cell movement.

Adherens Junctions↗
PubMedDate not supplied

The novel receptors that mediate the entry of herpes simplex viruses and animal alphaherpesviruses into cells.

An extended array of cell surface molecules serve as receptors for HSV entry into cells. In addition to the heparan sulphate glycosaminoglycans, which mediate the attachment of virion to cells, HSV requires an entry receptor. The repertoire of entry receptors into human cells includes molecules from three structurally unrelated molecular families. They are (i) HveA (herpesvirus entry mediator A), (ii) members of the nectin family, (iii) 3-O-sulphated heparan sulphate. The molecules have different attributes and play potentially different roles in HSV infection and spread to human tissues. All the human entry receptors interact physically with the virion envelope glycoprotein D (gD). (i) HveA is a member of the TNF-receptor family. It mediates entry of a restricted range of HSV strains. Its expression is restricted to few lineages (e.g. T-lymphocytes). (ii) The human nectin1alpha (HIgR), nectin1delta (PRR1-HveC), and the nectin2alpha (PRR2alpha-HveB) and nectin2delta (PRR2delta) belong to the immunoglobulin superfamily. They are homologues of the poliovirus receptor (CD155), with which they share the overall structure of the ectodomain. The human nectin1alpha-delta are broadly expressed in cell lines of different lineages, are expressed in human tissue targets of HSV infection, serve as receptors for all HSV-1 and HSV-2 strains tested and mediate entry not only of free virions, but also cell-to-cell spread of virus. (iii) The 3-O-sulphated heparan sulphate is expressed in some selected human cell lines (e.g. endothelial and mast cells) and human tissues, and mediates entry of HSV-1, but not HSV-2. The human nectin2alpha and nectin2delta serve as receptors for a narrow range of viruses. A characteristic of the human nectin1alpha-delta is the promiscuous species non-specific receptor activity towards the animal alphaherpesviruses, pseudorabies virus (PrV) and bovine herpesvirus 1 (BHV-1). By contrast with the human nectin1delta, its murine homologue (mNectin1delta) does not bind gD at detectable level, yet it mediates entry of HSV, as well as of PrV and BHV-1. This provides the first example of a mediator of HSV entry independent of a detectable interaction with gD.

Alphaherpesvirinae↗
PubMed1993

Adhesion molecule expression in human synovial tissue.

OBJECTIVE: We have previously shown that E-selectin is expressed on endothelium in rheumatoid arthritis (RA) synovial tissues, and hence may be important in recruitment of leukocytes into the inflamed joint. In the present study, we determined whether other cellular adhesion molecules, including selectins and members of the integrin and immunoglobulin supergene families, are expressed in frozen synovium. METHODS: We employed immunohistochemical staining to determine the distribution of CD31 (PECAM), CD44 (hyaluronate receptor), CD62 (P-selectin), Leu-8 (L-selectin), and the integrin subunits alpha 5 (VLA-5), alpha 6 (VLA-6), beta 1 (VLA 1-6), and beta 3 (vitro-nectin receptor), in synovial tissue from 9 RA and 9 osteoarthritis (OA) patients, and from 3 normal (NL) subjects. RESULTS: P-selectin was expressed on vascular endothelium in all synovial tissues examined. L-selectin and alpha 5-integrin, while expressed on a variety of cell types, were not differentially expressed on RA synovial tissues. Integrin subunits alpha 6 and beta 1 were down-regulated on some RA synovial tissue components. In contrast, CD31 was expressed to a greater extent on RA than on OA lining cells and macrophages (P < 0.05). CD44 was expressed to a greater extent on RA or OA macrophages, lining cells, and fibroblasts compared with NL (P < 0.05). Integrin subunit beta 3 was strongly expressed on RA synovial blood vessels compared with NL (P < 0.05). CONCLUSION: The expression of integrins VLA 1-6, and selectins P and L is not up-regulated in RA synovial tissues. CD31 and CD44 are up-regulated on RA macrophages and lining cells, CD44 on RA fibroblasts, and beta 3-integrin on RA blood vessels. The up-regulation of CD31, CD44, and beta 3-integrin in RA synovial tissues may help tip the balance of adhesive interactions toward passage and retention of leukocytes in the inflamed joint.

Antigens, Differentiation, Myelomonocytic↗
PubMed2026

Spatial Multiomics Reveal Insights Into ADC Efficacy.

Antibody-drug conjugates (ADCs) have transformed the therapeutic landscape of solid tumors; however, responses remain heterogeneous and complex to predict. In addition, a growing number of multiple ADC targets are either approved or in late-stage clinical development, such as NECTIN-4, HER2, or TROP2 for metastatic urothelial cancer. Spatial multiomics-representing next-generation methods that couple high-plex RNA sequencing and multiplex protein imaging with precise x-y-z coordinates within tissues-offer a direct way to correlate (ADC) antigen expression, cell state information, and micro-anatomical context with patient treatment outcomes. In this review, we highlight suitability and technological advancements in current spatial transcriptomics and proteomics approaches to decode modes of action and resistance to ADCs and extract biological insights, particularly in metastatic urothelial cancer-and propose an integrative framework that combines spatial readouts with machine and/or deep learning-driven analytics to stratify patients, forecast on- and off-target toxicities, and guide next-generation linker-payload designs or combination therapies.

Humans↗
PubMed2006

Tightly regulated induction of the adhesion molecule necl-5/CD155 during rat liver regeneration and acute liver injury.

TuAg1/TagE4, the rat ortholog of the human poliovirus receptor CD155, is expressed on a high percentage of rat hepatocellular carcinomas. Recent studies have shown that TuAg1/TagE4/CD155 is a member of the nectin family of immunoglobulin (Ig)-like cell adhesion molecules, designated necl-5. Necl-5 is present at exceedingly low levels in adult epithelial tissues but is upregulated in primary cultures of rat hepatocytes, suggesting that disruption of liver architecture triggers its expression. To explore this possibility, we examined expression of necl-5 after two-thirds partial hepatectomy or carbon tetrachloride (CCl4)-induced acute injury. Using quantitative real-time polymerase chain reaction (QPCR), we found that necl-5 mRNA levels increased 15-fold by 9 hours, and decreased to 4-fold above baseline by 24 hours after partial hepatectomy. Necl-5 mRNA levels increased over 100-fold 6 hours after treatment with CCl4, reaching a peak of 140-fold above baseline by 10 hours, and thereafter rapidly declining. Necl-5 was localized at the membrane of midlobular and centrilobular hepatocytes 10 to 48 hours after CCl4 exposure. Northern blot analysis demonstrated a close correlation between the kinetics of necl-5 expression and the immediate-early response gene c-myc. Subconfluent cultures of the non-transformed liver epithelial cell line WB-F344 expressed high levels of necl-5, which was down-regulated as cells approached confluence. The transformed WB-F344 line GP7TB did not demonstrate density-dependent regulation of necl-5 expression. In conclusion, we report the in vivo induction of necl-5 in rat hepatocytes and provide evidence that both necl-5 mRNA and protein are tightly regulated in adult epithelial cells and tissue.

Animals↗
PubMed2005

Interactions among IQGAP1, Cdc42, and the cadherin/catenin protein complex regulate Sertoli-germ cell adherens junction dynamics in the testis.

The movement of developing germ cells across the seminiferous epithelium during spermatogenesis involves extensive adherens junction (AJ) restructuring between Sertoli cells, as well as between Sertoli and germ cells. In this report, we show that the intricate interactions between Cdc42 (a Rho family protein of Mr approximately 23 kDa originally identified in membranes of human platelets and placenta, and is the homolog of CDC42Sc, which is known to regulate of bud-site assembly in Saccharomyces cerevisiae) and its effector, IQ motif containing GTPase activating protein (IQGAP1, Mr approximately 189 kDa, it is also an actin-binding protein known to interact with Cdc42 and Rac1 GTPases), regulate Sertoli-germ cell, but not Sertoli-Sertoli cell, AJ dynamics. Using testis lysates for immunoprecipitation (IP), IQGAP1 was shown to associate with E-cadherin, N-cadherin, and beta-catenin (but not beta1-integrin and nectin-2), as well as with actin and vimentin (but not alpha-tubulin). Moreover, IQGAP1 was found to localize to the periphery of both Sertoli and germ cells in the seminiferous epithelium, at sites of cell-cell contacts. Using fluorescent microscopy with dual fluorescent probes, IQGAP1 was found to co-localize, at least in part, with N-cadherin in the seminiferous epithelium consistent with their localization at the basal and apical ES. Using Sertoli-germ cell cocultures, it was demonstrated that AJ assembly associated with a transient induction of Cdc42 and IQGAP1, which was not found when Sertoli cells were cultured alone. Lastly, a shift in the interactions of Cdc42, IQGAP1, beta-catenin, and N-cadherin was detected in Sertoli-germ cell cocultures using an Ca2+-induced AJ disruption model, which was used to examine AJ disassembly and its reassembly. In the presence of Ca2+, IQGAP1 bound preferentially to Cdc42 rather than to beta-catenin. However, when Ca2+ was depleted from cocultures using EGTA, a Ca2+ chelating agent, IQGAP1 lost its affinity for Cdc42 and became tightly associated with beta-catenin, destabilizing cadherin-mediated AJs between Sertoli and germ cells. Yet this shift of protein-protein interaction was not detected in Sertoli cells cultured alone. These results illustrate that the interactions among IQGAP1, Cdc42, and beta-catenin are crucial to the regulation of Sertoli-germ cell, but not Sertoli-Sertoli cell, AJ dynamics in the seminiferous epithelium.

Adherens Junctions↗
PubMed2005

Myotubularin phosphoinositide phosphatases, protein phosphatases, and kinases: their roles in junction dynamics and spermatogenesis.

Spermatogenesis in the seminiferous epithelium of the mammalian testis is a dynamic cellular event. It involves extensive restructuring at the Sertoli-germ cell interface, permitting germ cells to traverse the epithelium from basal to adluminal compartment. As such, Sertoli-germ cell actin-based adherens junctions (AJ), such as ectoplasmic specializations (ES), must disassemble and reassemble to facilitate this event. Recent studies have shown that AJ dynamics are regulated by intricate interactions between AJ integral membrane proteins (e.g., cadherins, alpha6beta1 integrins and nectins), phosphatases, kinases, adaptors, and the underlying cytoskeleton network. For instance, the myotubularin (MTM) phosphoinositide (PI) phosphatases, such as MTM related protein 2 (MTMR2), can form a functional complex with c-Src (a non-receptor protein tyrosine kinase). In turn, this phosphatase/kinase complex associates with beta-catenin, a constituent of the N-cadherin/beta-catenin functional unit at the AJ site. This MTMR2-c-Src-beta-catenin complex apparently regulates the phosphorylation status of beta-catenin, which determines cell adhesive function conferred by the cadherin-catenin protein complex in the seminiferous epithelium. In this review, we discuss the current status of research on selected phosphatases and kinases, and how these proteins potentially interact with adaptors at AJ in the seminiferous epithelium to regulate cell adhesion in the testis. Specific research areas that are open for further investigation are also highlighted.

Adherens Junctions↗
PubMed2006

Adjudin-mediated junction restructuring in the seminiferous epithelium leads to displacement of soluble guanylate cyclase from adherens junctions.

A plethora of evidence supports the role of cyclic nucleotides in junction restructuring. For instance, studies have shown cGMP to be a key regulator of junction assembly and disassembly in different in vitro and in vivo systems. In this study, we examine the role of soluble guanylate cyclase (sGC) in junction restructuring in the seminiferous epithelium of the rat testis. First, the interaction of soluble guanylate cyclase beta1 (sGCbeta1; sGC is a heterodimer comprised of an alpha and a beta subunit) with proteins that constitute adherens and tight junctions in the testis was demonstrated. By immunoprecipitation, sGCbeta1 was found to associate with occludin, JAM-A, and ZO-1, as well as with cadherin, catenin, nectin, afadin, ponsin, and espin, suggestive of its role in cell junction dynamics. These results were corroborated in part by immunohistochemistry experiments, which revealed that the localization of sGCbeta1 was largely restricted to the site of the apical and basal ectoplasmic specialization. Next, the role of sGC in junction dynamics was addressed by using an in vivo model of junction restructuring. Administration of Adjudin--a chemical entity known to specifically perturb adhesion between Sertoli and germ cells (i.e., round and elongate(ing) spermatids and most spermatocytes)--resulted in a approximately 1.5-fold increase in sGCbeta1, coinciding with the loss of germ cells from the epithelium. More importantly, the ability of sGCbeta1 to associate with cadherin increased approximately three-fold during Adjudin-mediated restructuring of Sertoli-germ cell junctions, whereas its interaction with tight junction proteins (i.e., occludin and ZO-1) decreased. Taken collectively, these results suggest that sGC participates in the remodeling of cell junctions during spermatogenesis.

Adherens Junctions↗
PubMed2002

Kinetic analysis of glycoprotein C of herpes simplex virus types 1 and 2 binding to heparin, heparan sulfate, and complement component C3b.

Glycoprotein C (gC) from herpes simplex virus (HSV) facilitates virus entry by attaching the virion to host cell-surface heparan sulfate (HS). Although gC from HSV-1 (gC1) and from HSV-2 (gC2) bind to heparin, gC2 is believed to play a less significant role than gC1 in attachment of virus to cells. This attachment step is followed by the binding of gD to one of several cellular receptors. gC also plays an important role in immune evasion by binding to the C3b fragment of the third component of the host complement system. Yet, although both gC1 and gC2 protect HSV against complement-mediated neutralization, only gC on HSV-1-infected cells acts as a receptor for C3b. We used optical biosensor technology to quantitate the affinities (K(D)) and the stabilities (k(off)) between both serotypes of gC with heparin, HS, and C3b to address three questions concerning gC interactions. First, can differences in affinity or stability account for differences between the contributions of HSV-1 and HSV-2 gC in attachment? Our data show that the gC2-HS complex is highly unstable (k(off) = 0.2 s(-1)) compared to the gC1-HS complex (k(off) = 0.003 s(-1)), suggesting why gC2 may not play an important role in attachment of virus to cells as does gC1. Second, does gC2 have a lower affinity for C3b than does gC1, thereby explaining the lack of C3b-receptor activity on HSV-2 infected cells? Surprisingly, gC2 had a 10-fold higher affinity for C3b compared to gC1, so this functional difference in serotypes cannot be accounted for by affinity. Third, do differences in gC-HS and gD-receptor affinities support a model of HSV entry in which the gC-HS interaction is of lower affinity than the gD-receptor interaction? Our biosensor results indicate that gC has a higher affinity for HS than gD does for cellular receptors HveA (HVEM) and HveC (nectin-1).

Binding Sites↗
PubMed1984

Hyaluronate binding proteins also bind to fibronectin, laminin and collagen.

Small molecular weight proteins, isolated from the culture medium of embryonic chick heart fibroblasts and 3T3 cell lines by hyaluronate affinity chromatography, bind in order of apparent affinity, to hyaluronate, fibronectin, collagen and laminin. Such proteins isolated from the MSV-transformed 3T3 cell line bind in greater amounts to the nectins and hyaluronate than do similar proteins isolated from heart fibroblasts or 3T3 cells. These small hyaluronate binding proteins are immunologically distinct from other well characterized proteins such as laminin, fibronectin, bovine serum albumin and actin. Their relationship to other small, extracellular proteins and their possible role in structuring of extracellular matrix are discussed.

Animals↗
PubMed1995

Transforming growth factor-beta 1 downregulates dexamethasone-induced tetranectin gene expression during the in vitro mineralization of the human osteoblastic cell line SV-HFO.

In the present study, we examined the regulation of tetranectin gene expression using a human osteoblastic cell line, SV-HFO, that undergoes mineralization upon treatment with dexamethasone. We found that the expression of tetranectin and alkaline phosphatase mRNA was induced by dexamethasone treatment as evidenced by Northern blotting. When transforming growth factor-beta 1 (TGF-beta 1) was added together with dexamethasone to the SV-HFO cell cultures, the mineralization process was markedly suppressed and the expression of tetra nectin and alkaline phosphatase was downregulated in a dose-dependent manner. These results demonstrate that the expression of tetranectin in these osteoblastic cells is regulated by dexamethasone and TGF-beta 1 and that tetranectin expression is tightly linked to the process of mineralization.

Biomarkers, Tumor↗
PubMed1993

Integrins alpha v beta 3 and alpha v beta 5 promote adenovirus internalization but not virus attachment.

Adenovirus contains a heterodimeric protein complex consisting of 186 kd fiber protein that mediates high affinity virus attachment to cells and a 400 kd pentavalent subunit (penton base) that contains five Arg-Gly-Asp sequences, implying a role for integrins in adenovirus infection. We demonstrate that the vitro-nectin-binding integrins alpha v beta 3 and alpha v beta 5 promote viral infection in a novel way since antibodies against these receptors or soluble penton base block virus internalization without affecting attachment. Moreover, adenovirus binds to cultured cells lacking alpha v integrins but fail to become internalized, thus restricting infection of these cells. Transfection of alpha v(-) cells with a cDNA encoding alpha v results in the expression of integrins alpha v beta 3 and alpha v beta 5 and allows virus internalization and infection. These data indicate that adenovirus attachment and uptake into cells are separate but cooperative events that result from the interaction of distinct viral coat proteins with a receptor for attachment and alpha v integrin receptors for internalization.

Adenoviruses, Human↗
PubMed2005

Identification and characterization of murine DNAM-1 (CD226) and its poliovirus receptor family ligands.

The leukocyte adhesion molecule DNAM-1 (CD226) is a member of the immunoglobulin superfamily and constitutively expressed on the majority of CD4+ and CD8+ T lymphocytes, natural killer (NK) cells, monocytes/macrophages, and a subset of B lymphocytes. The poliovirus receptor (PVR; CD155) and its family member nectin 2 (CD112) have recently been identified as the ligands for DNAM-1. Interaction of DNAM-1 with the ligands induces NK cell- and CD8+ T cell-mediated cytotoxicity and cytokine secretion. However, in vivo function of the receptor-ligand interaction has remained unclear. Here, we identified murine DNAM-1 and PVR homologues that physically and functionally bind each other. We demonstrated that ligand binding of murine DNAM-1 induced a costimulatory signal in antigen-specific CD8+ T cells. These results should provide a useful animal model to explore a role of DNAM-1 in immune responses in vivo.

Amino Acid Sequence↗
PubMed2026

Antibody-drug conjugates against multidrug-resistant cancers: Biomarker-guided patient selection, payload engineering, linker chemistry, and bystander effects.

Antibody-drug conjugates (ADCs) are one of the most significant advancements in modern cancer therapeutics. Combining the target selectivity of monoclonal antibodies with the cytotoxic potential of payloads, ADCs effectively kill cancer cells and offer hope to patients with even refractory cancer types. Beyond simply increasing the number of therapeutic options available for cancer patients, ADCs have become a powerful frontline agent in overcoming multidrug resistance (MDR). As one of the most challenging obstacles to effective cancer care, MDR is mediated by ATP-binding cassette (ABC) transporter-mediated drug efflux, target-based mutations, and dysregulated apoptosis. The clinical success of ADCs specifically engineered to overcome MDR, including in heterogeneous tumors and cancer cells that exhibit bypass signaling, is well established. This is especially evident with trastuzumab deruxtecan (T-DXd) in HER2-low, HER2-positive, and HER2-mutant cancers; sacituzumab govitecan (SG) in TROP2-expressing triple-negative breast cancer (TNBC) and urothelial carcinoma; and enfortumab vedotin in Nectin-4-positive bladder cancer. By overcoming MDR, ADCs have enabled more effective treatment algorithms across multiple malignancies. Most importantly, the clinical application of ADCs has become inextricably linked to cancer genomics. HER2 testing has evolved from a two-tiered system to a continuous spectrum including HER2-ultralow, HER2-low, HER2-positive, and ERBB2-mutant categories. Each of these categories exhibits different eligibility guidelines for ADC patient selection. As cancer cells continue to evolve and develop resistance to even ADCs through mutations and variants, researchers and clinicians have used pharmacogenomics to predict ADC response and resistance. To define the genomic architecture of ADC-resistant tumor subpopulations, single-cell transcriptomic studies and liquid biopsy approaches are being used to enable real-time examination of the tumor genome during ADC therapy, thereby optimizing treatment and circumventing resistance driven by emerging mutations and variants. This review provides a comprehensive analysis of the molecular structure of ADCs, the pharmacological principles underlying their potent cytotoxic activity against MDR cancer cells, the genomic and transcriptomic biomarkers that guide ADC patient selection, and the emerging resistance mechanisms that will shape the next generation of promising ADC development.

Humans↗