Abstract
Our previous studies demonstrated that the proinflammatory peptide, macrophage migration inhibitory factor (MIF), functions as an autocrine mediator of both growth factor- and integrin-dependent sustained ERK MAPK activation, cyclin D1 expression, and cell cycle progression. We now report that MIF promotes the activation of the canonical ERK MAPK cascade and cyclin D1 expression by stimulating the activity of the Rho GTPase and downstream signaling to stress fiber formation. Rho-dependent stress fiber accumulation promotes the sustained activation of ERK and subsequent cyclin D1 expression during G(1)-S phase cell cycle progression. This pathway is reported to be dependent upon myosin light chain (MLC) kinase, integrin clustering, and subsequent activation of focal adhesion kinase, leading to sustained MAPK activity. Our studies reveal that recombinant MIF induces cyclin D1 expression in a Rho-, Rho kinase-, MLC kinase-, and ERK-dependent manner in asynchronous NIH 3T3 fibroblasts. Moreover, MIF(-/-) murine embryonic fibroblasts display aberrant cyclin D1 expression that is linked to defective Rho activity, stress fiber formation, and MLC phosphorylation. These results suggest that MIF is an integral autocrine mediator of Rho GTPase-dependent signaling events and provide mechanistic insight into how MIF regulates proliferative, migratory, and oncogenic processes.
Highlights
Despite being one of the earliest cytokines discovered, macrophage migration inhibitory factor (MIF)1 is arguably the least understood
We have found that MIF-deficient cells display defective growth factor/adhesion-induced sustained extracellular signal-regulated kinase (ERK) activation, leading to cyclin D1 expression, Rb inactivation, and S phase cell cycle progression [5]
We have demonstrated that MIF is a central participant in the maintenance of steady state cyclin D1 expression in immortalized rodent fibroblasts
Summary
Despite being one of the earliest cytokines discovered, macrophage migration inhibitory factor (MIF)1 is arguably the least understood. We report that MIF promotes the activation of the canonical ERK MAPK cascade and cyclin D1 expression by stimulating the activity of the Rho GTPase and downstream signaling to stress fiber formation.
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