Lichen planus (LP) is a chronic inflammatory disorder that most often affects middle-aged adults. LP can involve the skin or mucous membranes including the oral, vulvovaginal, esophageal, laryngeal, and conjunctival mucosa. It has different variants based on the morphology of the lesions and the site of involvement. The literature suggests that certain presentations of the disease such as esophageal or ophthalmological involvement are underdiagnosed. The burden of the disease is higher in some variants including hypertrophic LP and erosive oral LP, which may have a more chronic pattern. LP can significantly affect the quality of life of patients as well. Drugs or contact allergens can cause lichenoid reactions as the main differential diagnosis of LP. LP is a T-cell mediated immunologic disease but the responsible antigen remains unidentified. In this paper, we review the history, epidemiology, and clinical subtypes of LP. We also review the histopathologic aspects of the disease, differential diagnoses, immunopathogenesis, and the clinical and genetic correlations.
Integrin-growth factor receptor cross-talk plays a role in growth factor signaling, but the specifics are unclear. In a current model, integrins and growth factor receptors independently bind to their ligands (extracellular matrix and growth factors, respectively). We discovered that neuregulin-1 (NRG1), either as an isolated EGF-like domain or as a native multi-domain form, binds to integrins ␣v3 (with a K D of 1.36 ؋ 10 ؊7 M) and ␣64. Docking simulation predicted that three Lys residues at positions 180, 184, and 186 of the EGF-like domain are involved in integrin binding. Mutating these residues to Glu individually or in combination markedly suppressed integrin binding and ErbB3 phosphorylation. Mutating all three Lys residues to Glu (the 3KE mutation) did not affect the ability of NRG1 to bind to ErbB3 but markedly reduced the ability of NRG1 to induce ErbB3 phosphorylation and AKT and Erk1/2 activation in MCF-7 and T47D human breast cancer cells. This suggests that direct integrin binding to NRG1 is critical for NRG1/ErbB signaling. Notably, stimulation of cells with WT NRG1 induced co-precipitation of ErbB3 with ␣64 and with ␣v3 to a much lower extent. This suggests that WT NRG1 induces integrin-NRG1-ErbB3 ternary complex formation. In contrast, the 3KE mutant was much less effective in inducing ternary complex formation than WT NRG1, suggesting that this process depends on the ability of NRG1 to bind to integrins. These results suggest that direct NRG1-integrin interaction mediates integrin-ErbB cross-talk and that ␣64 plays a major role in NRG-ErbB signaling in these cancer cells.The neuregulins (NRGs) 2 are a family of four structurally related proteins that are part of the EGF family of proteins (NRG1-4) (1-4). Transmembrane NRGs typically function as precursor molecules that are cleaved by metalloproteases. This results in the release of the extracellular domain that may subsequently bind to nearby receptors (autocrine/paracrine action). NRGs contain an epidermal growth factor (EGF)-like motif that binds and activates receptor-tyrosine kinases in the EGF receptor (ErbBs) family. Neuregulin-1 (NRG1) binds to ErbB3 and ErbB4. NRG1 has 11 isoforms (5). NRG1 plays essential roles in the nervous system, heart, and breast. NRG1 signaling is involved in the development and functions of several other organ systems and human diseases, including schizophrenia (6), coronary heart diseases (7), and cancer (8). Targeted deletion of ErbB2, ErbB3, ErbB4, or NRG1 in mice leads to developmental abnormalities that are severe in the nervous system and lethal in the cardiovascular system (9 -11). In cancer the interaction between ErbB receptors and ligands such as NRGs plays an important role in tumor growth. The EGF-like motif of NRGs is essential and sufficient for receptor binding and activation as well as promoting tumorigenesis (12). The presence of the autocrine loop is one of the causes that induces aberrant ErbB receptor activation and has been correlated with cancer development and progression. Disrupting...
Contact stomatitis occurs in up to 10% of the population. Mechanical or chemical irritation, ill-fitting dentures, and dental fillings can induce irritant contact stomatitis. Type I hypersensitivity and type IV hypersensitivity to dental products and foods are frequently responsible for the allergic types of contact stomatitis. We review the causal agents of contact stomatitis, the differential diagnoses, diagnostic testing, and potential treatment.
Leukocyte arrest on the endothelial cell surface during leukocyte extravasation is induced by rapid integrin activation by chemokines. We recently reported that fractalkine induces integrin activation without its receptor CX3CR1 through binding to the allosteric site (site 2) of integrins. Peptides from site 2 bound to fractalkine and suppressed integrin activation by fractalkine. We hypothesized that this is not limited to membrane-bound fractalkine. We studied whether stromal cell-derived factor-1 (SDF1), another chemokine that plays a critical role in leukocyte arrest, activates integrins through binding to site 2. We describe here that (1) SDF1 activated soluble integrin αvβ3 in cell-free conditions, suggesting that SDF1 can activate αvβ3 without CXCR4; (2) site 2 peptide bound to SDF1, suggesting that SDF1 binds to site 2; (3) SDF1 activated integrins αvβ3, α4β1, and α5β1 on CHO cells (CXCR4-negative) and site 2 peptide suppressed the activation; (4) A CXCR4 antagonist AMD3100 did not affect the site 2-mediated integrin activation by SDF1; (5) Cell-surface integrins were fully activated in 1 min (much faster than activation of soluble αvβ3) and the activation lasted at least for 1 h. We propose that the binding of SDF1 to cell-surface proteoglycan facilitates the allosteric activation process; (6) Mutations in the predicted site 2-binding site in SDF1 suppressed integrin activation. These results suggest that SDF1 (e.g. presented on proteoglycans) can rapidly activate integrins in an allosteric manner by binding to site 2 in the absence of CXCR4. The allosteric integrin activation by SDF1 is a novel target for drug discovery.
Background: Integrin ␣v3-extracellular matrix interaction and/or ␣v3 binding to insulin-like growth factor-1 (IGF1; and integrin-IGF1-IGF1 receptor ternary complex formation) is critical for IGF signaling. Results: ␣64 directly bound to IGF1 and mediated IGF1 signaling through ternary complex formation. ␣64 is required when cell-matrix adhesion is reduced or in three-dimensional culture. Conclusion: ␣64-IGF1 binding is important for IGF signaling in anchorage-independent conditions. Significance: The integrin-IGF interaction is a novel therapeutic target.
The duration and strength of the dopaminergic signal is regulated by the dopamine transporter (DAT). Drug addiction, neurodegenerative and neuropsychiatric diseases have all been associated with altered DAT activity. The membrane localization and the activity of DAT are regulated by a number of intracellular proteins. α-synuclein, a protein partner of DAT, is implicated in neurodegenerative disease and drug addiction. Little is known about the regulatory mechanisms of the interaction between DAT and α-synuclein, the cellular location of this interaction, and the functional consequences of this interaction on the basal, amphetamine (AMPH) induced DAT-meditated DA efflux and membrane microdomain distribution of the transporter. Here, we found that the majority of DAT/α-synuclein protein complexes are found at the plasma membrane of dopaminergic neurons or mammalian cells, and that AMPH-mediated increase in DAT activity enhances the association of these proteins at the plasma membrane. Further examination of the interaction of DAT and α-synuclein revealed a transient interaction between these two proteins at the plasma membrane. Additionally, we found DAT-induced membrane depolarization enhances plasma membrane localization of α-synuclein, which in turn increases DA efflux and enhances DAT localization in cholesterol rich membrane microdomains.
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