Medicine and Health Sciences Commons^™

Negative Regulation Of Urokinase Receptor Activity By A Gpi-Specific Phospholipase C In Breast Cancer Cells., Michiel Van Veen, Elisa Matas-Rico, Koen Van De Wetering, Daniela Leyton-Puig, Katarzyna M. Kedziora, Valentina De Lorenzi, Yvette Stijf-Bultsma, Bram Van Den Broek, Kees Jalink, Nicolai Sidenius, Anastassis Perrakis, Wouter H. Moolenaar

Department of Dermatology and Cutaneous Biology Faculty Papers

The urokinase receptor (uPAR) is a glycosylphosphatidylinositol (GPI)-anchored protein that promotes tissue remodeling, tumor cell adhesion, migration and invasion. uPAR mediates degradation of the extracellular matrix through protease recruitment and enhances cell adhesion, migration and signaling through vitronectin binding and interactions with integrins. Full-length uPAR is released from the cell surface, but the mechanism and significance of uPAR shedding remain obscure. Here we identify transmembrane glycerophosphodiesterase GDE3 as a GPI-specific phospholipase C that cleaves and releases uPAR with consequent loss of function, whereas its homologue GDE2 fails to attack uPAR. GDE3 overexpression depletes uPAR from distinct basolateral membrane domains in …

Proteoglycans In Health And Disease: Novel Regulatory Signaling Mechanisms Evoked By The Small Leucine-Rich Proteoglycans., Renato V. Iozzo, Liliana Schaefer

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The small leucine-rich proteoglycans (SLRPs) are involved in many aspects of mammalian biology, both in health and disease. They are now being recognized as key signaling molecules with an expanding repertoire of molecular interactions affecting not only growth factors, but also various receptors involved in controlling cell growth, morphogenesis and immunity. The complexity of SLRP signaling and the multitude of affected signaling pathways can be reconciled with a hierarchical affinity-based interaction of various SLRPs in a cell- and tissue-specific context. Here, we review this interacting network, describe new relationships of the SLRPs with tyrosine kinase and Toll-like receptors and critically …

Cell Autonomous Expression Of Inflammatory Genes In Biologically Aged Fibroblasts Associated With Elevated Nf-Kappab Activity., Andres Kriete, Kelli L Mayo, Nirupama Yalamanchili, William Beggs, Patrick Bender, Csaba Kari, Ulrich Rodeck

Department of Dermatology and Cutaneous Biology Faculty Papers

BACKGROUND: Chronic inflammation is a well-known corollary of the aging process and is believed to significantly contribute to morbidity and mortality of many age-associated chronic diseases. However, the mechanisms that cause age-associated inflammatory changes are not well understood. Particularly, the contribution of cell stress responses to age-associated inflammation in 'non-inflammatory' cells remains poorly defined. The present cross-sectional study focused on differences in molecular signatures indicative of inflammatory states associated with biological aging of human fibroblasts from donors aged 22 to 92 years. RESULTS: Gene expression profiling revealed elevated steady-state transcript levels consistent with a chronic inflammatory state in fibroblast cell-strains …

A Domain-Oriented Approach To The Reduction Of Combinatorial Complexity In Signal Transduction Networks, Holger Conzelmann, Julio Saez-Rodriguez, Thomas Sauter, Boris N. Kholodenko Phd, Dsci, Ernst D. Gilles

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Background:

Receptors and scaffold proteins possess a number of distinct domains and bind multiple partners. A common problem in modeling signaling systems arises from a combinatorial explosion of different states generated by feasible molecular species. The number of possible species grows exponentially with the number of different docking sites and can easily reach several millions. Models accounting for this combinatorial variety become impractical for many applications.

Results:

Our results show that under realistic assumptions on domain interactions, the dynamics of signaling pathways can be exactly described by reduced, hierarchically structured models. The method presented here provides a rigorous way to …