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β-adrenergic receptor (β-AR) stimulation increases extracellular levels of ubiquitin (UB), and exogenous UB plays an important role in β-AR-stimulated myocardial remodeling with effects on heart function, fibrosis and myocyte apoptosis. Cardiac fibroblasts are vital for maintaining the normal function of the heart, and in the structural remodeling of the heart in response to injury. Here we hypothesized that extracellular UB modulates cardiac fibroblast phenotype and function via its interaction with CXC chemokine receptor type 4 (CXCR4).Serum starved adult cardiac fibroblasts were used to identify CXCR4 as a receptor for UB. Fluorescent microscopy, co-immunoprecipitation, western blot, proliferation, migration and collagen contraction assays were performed to investigate the role of UB/CXCR4 axis on cell signaling, and modulation of fibroblast phenotype and function.Using fluorescent microscopy and co-immunoprecipitation assay, we provide evidence that extracellular UB interacts with CXCR4. CXCR4 antagonist, AMD3100, inhibited interaction of UB with CXCR4. UB activated ERK1/2, not Akt. It enhanced VEGF-A expression, while decreasing β3 integrins expression. Two mutated UB proteins (V70A and F4A; unable to interact with CXCR4) failed to affect the expression of VEGF-A and β3 integrins. UB treatment inhibited migration of cells into the wound and FBS-stimulated cell proliferation. UB enhanced expression of α-smooth muscle actin (marker of myofibroblast differentiation) and contraction of fibroblast-populated collagen gel pads. Most of the effects of UB were negated by AMD3100.The data presented here suggest that UB interacts with CXCR4, and UB/CXCR4 interaction affects intracellular signaling, and modulates fibroblast phenotype and function.