The urokinase-type plasminogen activator (uPA) receptor (uPAR) functions in concert with co-receptors, including integrins, FPR-like receptor-1/lipoxin A4 receptor, and the epidermal growth factor receptor (EGFR), to initiate cell signaling. uPAR co-receptors may be dynamically organized into a multiprotein signaling receptor complex. In Chinese hamster ovary-K1 (CHO-K1) cells, uPA-binding to uPAR activates ERK/ MAP kinase, even though these cells do not express the EGFR; however, when CHO-K1 cells are transfected to express the EGFR, ERK activation becomes EGFR-dependent. In this study, we demonstrate that ERK activation in response to uPA follows equivalent biphasic kinetics in EGFR-expressing and -deficient CHO-K1 cells. In both cell types, the response is pertussis toxinsensitive; however, uPA promotes cell proliferation exclusively in the EGFR-expressing cells. uPA-induced mitogenic activity requires activation of both STAT5b and ERK. STAT5b was tyrosine-phosphorylated, in response to uPA, only in EGFR-expressing cells. uPA-induced cell proliferation was blocked by dominant-negative MEK1, dominant-negative STAT5b, and by expression of an EGFR that is mutated at Tyr-845, which is essential for STAT5b activation. In two cell culture models of uPAstimulated breast cancer growth, MDA-MB 468 cells treated with uPA and MCF-7 cells treated with uPAplasminogen activator inhibitor-1 complex, proliferation was completely inhibited when EGFR expression or activity was blocked. We conclude that expression and assembly of uPAR co-receptors in a specific cell type determines the response to uPA. The EGFR selectively cooperates with uPAR to mediate mitogenesis.Receptor transactivation provides a mechanism by which an expanded continuum of signaling pathways may be activated in response to a single ligand. The epidermal growth factor receptor (EGFR) 1 plays a prominent role in transactivation events initiated by G protein-coupled receptors (GPCRs), integrins, and cytokine receptors (1-3). Transactivated EGFR frequently is responsible for activating Ras and extracellular signal-regulated kinase/MAP kinase (ERK) (1-3). EGFR transactivation may be ligand-dependent, in which case membrane-associated metalloproteases release EGFR ligands from their transmembrane anchors (4, 5), or ligand-independent, due to the activity of intracellular kinases, such as c-Src, which cause EGFR tyrosine phosphorylation (6). The urokinase receptor (uPAR) has two distinct ligands, urokinase-type plasminogen activator (uPA) and vitronectin, which activate distinct cell-signaling pathways. Vitronectin activates the small GTPase, Rac1, and thereby regulates downstream factors involved in new actin polymerization (7-9). uPA activates multiple kinases and, perhaps most importantly, ERK (10 -13). ERK activation occurs in response to low uPAR fractional occupancy, even in cells that express minimum amounts of uPAR, accounting for the role of uPAR autocrine signaling in determining the basal level of activated ERK in many cells (9,13,14). In MCF-7 breast ...

Both the relative volume of liquid monomer and the timing of antibiotic addition have substantial effects on the elution of antibiotic from bone cement.

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When planning anterior lumbar spine surgery, careful review of the vascular anatomy on imaging should be performed. This will help prepare the surgeon for more complex or anomalous anterior anatomy. If atypical vascular anatomy is identified, consideration of a pathologic cause should be investigated.