Signal Transduction
T-cadherin – a guide and guard during tissue remodelling
Cadherins are a superfamily of cell-surface proteins involved in cell-cell interactions and signaling. They exhibit cell-type and developmental specificity in expression and are aberrantly regulated in several human malignancies. Atypical GPI-anchored T-cadherin (T-cad) is present in many tissues/cell types. While abnormal (high or low) expression has been associated with a variety of diseases, biomolecular characteristics of T-cad, its function in different cell types/tissues and mechanisms of signaling are poorly understood. Our studies suggest T-cad is multifunctional with tissue-specific and context-dependent facets.
Role of T-cad in the vasculature
Expression, function and signal transduction in endothelial cells (EC). T-cad is expressed in the vessel and is increased during atherosclerosis, restenosis and pathological angiogenesis in vivo, and on proliferating EC and EC subjected to oxidative (OX) and endoplasmic reticulum (ER) stress in vitro. Upregulation on EC is thus characteristic of activation and stress. Collectively, our data suggest this offers a protective mechanism for limiting tissue damage during disease progression. T-cad influences many aspects of EC phenotype/behaviour, including proliferation, motility, angiogenesis and survival under conditions of OX and ER stress (Fig. 1). Intracellular signaling effectors for T-cad in EC include PI3K/Akt/ GSK3β, mTOR/S6K1, p38MAPK, β-catenin, RhoA and Rac1, integrin linked kinase (Fig. 1). Mem- brane adaptors enabling inward signaling by T-cad include Grp78/BiP and integrin β3 (Fig. 1). We found T-cad present in culture media and human plasma as a surface component of activated/apoptotic EC-derived plasma membrane-derived vesicles, termed microparticles (MP), which are considered a circulating hall- mark of EC activation/damage. Elevated levels of plasma T-cad associated with endothelium dysfunction (Fig.2), even in non-significant atherosclerosis, implicating T-cad as a biomarker for early atherogenesis. MP-bound T-cad induces survival signaling and angiogenic behavior in target EC via homophilic interactions. Interaction of plasma-delivered MP-bound T-cad with the luminal endothelium, accompanied by upregulation of T-cad on ac- tivated/injured EC, represents a novel biological protective mechanism of action for T-cad. Ongoing studies address the role of T-cad in a broader context of cardiovascular diseases and their complications.
Biomolecular analyses.
By transducing EC with domain-deletion mutants of T-cad and comparison of proangiogenic functions/signaling, we found EC1 and EC5 domains of T-cad to be essential for its proangiogenic effects. Dominant-negative mutants of T-cad are potential tools targeting excessive angiogenesis.
Transcriptional regulation of T-cad is poorly understood. We identified redox- sensitive regulatory elements within the minimal promoter region of T-cad in EC and a requirement for Trx-1 (thioredoxin-1) in OX stress-induced T-cad expression. Trx-1-dependent activation of T-cad gene expression during OX stress represents a novel anti-apoptotic mechanism for Trx-1.
Role of T-cad in non-melanoma skin cancers
We initiated studies on the role of T-cad in keratinocytes and in progression and malignant transformation of non-melanoma skin cancers (NMSC). In the healthy epidermis T-cad expression is restricted to the basal keratinocyte lay- er. Staining patterns for T-cad in NMSC suggest crucial regulatory functions in tumor demarcation, directional invasion and progression. In particular,
aberrant/absent T-cad associates with histologic features of a more malignant and invasive phenotype. Lentivector-based studies in keratinocyte and NMSC cell lines revealed that loss of T-cad is a major determinant in the acquisition of aggressive invasive behavior (Fig. 3). The functional outcome of change in T-cad expression in NMSC (loss = promigratory) is opposite to that observed for EC (gain=promigratory), but preliminary data suggest common mechanisms involving regulation of growth factor receptor activity/trafficking. In vitro/in vivo analyses on the role of T-cad in tumor expansion and angiogenesis and tumor cell extravasation/metastasis are ongoing.
Prof. Dr. Paul Erne
Division of Cardiology Kantonsspital Luzern
Improving detection of early atherosclerosis and the vulnerable patient
Atherosclerosis is a common, chronic and progressive disease of large arteries and is a leading cause of morbidity and mortality. Its prevalence is predicted to rise due to the increase of diabetes and obesity. Myocardial infarction, stroke or other cardiovascular events identify vulnerable patients who suffer from symptomatic arteriosclerosis. However, atherosclerosis is clinically silent long before plaque rupture and ensuing cardiovascular events, and recent intravascular ultrasound (IVUS) studies show a high incidence of coronary atherosclerotic lesions even in asymptomatic teenagers and young adults. De- tection of both the development of atherosclerosis at its non-significant stages as well as the shift from “indolent disease” to acute ischemic disease carries great clinical benefit, yet remains a diagnostic challenge. Atherosclerosis profiling using a multi- marker diagnostic paradigm comprising physical characteristics and lesional composition of vessels, endothelium function, plasma biomarkers of endothelial damage/dysfunction and inflammatory status and specific relationships between these parameters (e.g. Fig. 2) could improve risk stratification of patients and determination of treatment measures. We have compiled a wide-ranging clinical data base on a large cohort of study subjects (including healthy individuals, patients without cardiovascular risk factors, and patients with different stages of atherosclerosis defined on the basis of angiographic and IVUS data) and a corresponding bank of plasma samples and blood leukocyte isolates for biomarker analysis.
