Urokinase-type plasminogen activator receptor (uPAR) expression is elevated during inflammation and tissue remodelling and in many human cancers, in which it frequently indicates poor prognosis. uPAR regulates proteolysis by binding the extracellular protease urokinase-type plasminogen activator (uPA; also known as urokinase) and also activates many intracellular signalling pathways. Coordination of extracellular matrix (ECM) proteolysis and cell signalling by uPAR underlies its important function in cell migration, proliferation and survival and makes it an attractive therapeutic target in cancer and inflammatory diseases. uPAR lacks transmembrane and intracellular domains and so requires transmembrane co-receptors for signalling. Integrins are essential uPAR signalling co-receptors and a second uPAR ligand, the ECM protein vitronectin, is also crucial for this process.

Proinflammatory cytokines are frequently observed in the tumor microenvironment, and chronic inflammation is involved in cancer initiation and progression. We show that cytokine signaling through the receptor subunit GP130-IL6ST and the kinase JAK1 generates actomyosin contractility through Rho-kinase dependent signaling. This pathway generates contractile force in stromal fibroblasts to remodel the extracellular matrix to create tracks for collective migration of squamous carcinoma cells and provides the high levels of actomyosin contractility required for migration of individual melanoma cells in the rounded, "amoeboid" mode. Thus, cytokine signaling can generate actomyosin contractility in both stroma and tumor cells. Strikingly, actomyosin contractility itself positively modulates activity of the transcription factor STAT3 downstream of JAK1, demonstrating positive feedback within the signaling network.

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