Soluble Urokinase-type Plasminogen Activator Receptor Inhibits Cancer Cell Growth and Invasion by Direct Urokinase-independent Effects on Cell Signaling

Abstract

The urokinase-type plasminogen activator receptor (uPAR) is released from human cancers and is readily detected in blood. In animal models, soluble uPAR (Su-PAR) antagonizes cancer progression; however, the mechanism by which SuPAR functions in vivo remains unclear. It is generally thought that SuPAR scavenges uPA and prevents its interaction with membrane-anchored uPAR. In this study, we demonstrate a novel molecular mechanism by which SuPAR may inhibit cancer progression. We show that SuPAR has the potential to directly and in a uPA-independent manner block the signaling activity of membrane-anchored uPAR. Whether SuPAR inhibits signaling is cell type-specific, depending on the state of the endogenous uPA-uPAR signaling system. In uPAR-deficient cells that lack endogenous uPAR signaling, including uPAR؊/؊ murine embryonic fibroblasts and human embryonal kidney 293 cells, SuPAR functions as a partial signaling agonist that activates ERK/mitogen-activated protein kinase. By contrast, in cells with potent autocrine uPA-uPAR signaling systems, including MDA-MB 231 breast cancer cells and low density lipoprotein receptor-related protein-1-deficient murine embryonic fibroblasts, SuPAR substantially decreases ERK activation. The mechanism probably involves competitive displacement of membrane-anchored uPAR-uPA complex from signaling adaptor proteins. As a result of its effects on cell signaling, SuPAR blocks cell growth and inhibits cellular invasion of Matrigel TM . Cleavage of SuPAR by proteinases increases its signaling agonist activity and reverses its inhibitory effects on growth and invasion. Thus, proteolytic cleavage represents a molecular switch that neutralizes the anticancer activity of SuPAR.

Dynamic Assembly of the Urokinase-type Plasminogen Activator Signaling Receptor Complex Determines the Mitogenic Activity of Urokinase-type Plasminogen Activator

“…In support of this hypothesis, soluble uPAR has been shown to activate cell signaling similarly to uPA (15)(16)(17)(18). Furthermore, multiple signaling receptors have been co-immunoprecipitated or co-localized with cell surface uPAR, including integrins, FPR-like receptor-1/lipoxin A4 receptor (FPRL-1), and the EGFR (7,13,19,20).…”

Soluble Urokinase Receptor Is Released Selectively by Glioblastoma Cells That Express Epidermal Growth Factor Receptor Variant III and Promotes Tumor Cell Migration and Invasion*

“…We previously demonstrated that suPAR may function as a cell signaling agonist or antagonist depending on whether membrane-anchored uPAR in the target cell is actively engaged in cell signaling (27). The basal state of activation of signaling factors such as ERK1/2 in the target cell also is important (27).…”

“…The basal state of activation of signaling factors such as ERK1/2 in the target cell also is important (27). suPAR may compete with membrane-anchored uPAR for coreceptors such as FPRL-1 (6).…”

“…A number of studies have demonstrated that suPAR binds directly to membrane proteins, such as FPRL1, and triggers cell signaling (6,(27)(28)(29). The nature of the signaling response may be determined by whether suPAR is cleaved between domain-1 and the domain-2-3 region, revealing the epitope, SRSRY, involved in FPRL1 binding (6,27,30). suPAR has been implicated in hematopoietic stem cell mobilization (31) and in the development of focal segmental glomerulosclerosis (32).…”

A shed form of LDL receptor–related protein–1 regulates peripheral nerve injury and neuropathic pain in rodents

“…There is precedent for soluble forms of cellular receptors as direct regulators of cell physiology. The soluble form of the urokinase receptor, uPAR, regulates activation of ERK/MAPK and thereby controls cell growth and cell migration (66).…”