Mutations in SRPX2 (Sushi-Repeat Protein, X-linked 2) cause rolandic epilepsy with speech impairment (RESDX syndrome) or with altered development of the speech cortex (bilateral perisylvian polymicrogyria). The physiological roles of SRPX2 remain unknown to date. One way to infer the function of SRPX2 relies on the identification of the as yet unknown SRPX2 protein partners. Using a combination of interactome approaches including yeast two-hybrid screening, co-immunoprecipitation experiments, cell surface binding and surface plasmon resonance (SPR), we show that SRPX2 is a ligand for uPAR, the urokinase-type plasminogen activator (uPA) receptor. Previous studies have shown that uPAR(-/-) knock-out mice exhibited enhanced susceptibility to epileptic seizures and had brain cortical anomalies consistent with altered neuronal migration and maturation, all features that are reminiscent to the phenotypes caused by SRPX2 mutations. SPR analysis indicated that the p.Y72S mutation associated with rolandic epilepsy and perisylvian polymicrogyria, led to a 5.8-fold gain-of-affinity of SRPX2 with uPAR. uPAR is a crucial component of the extracellular plasminogen proteolysis system; two more SRPX2 partners identified here, the cysteine protease cathepsin B (CTSB) and the metalloproteinase ADAMTS4, are also components of the extracellular proteolysis machinery and CTSB is a well-known activator of uPA. The identification of functionally related SRPX2 partners provides the first and exciting insights into the possible role of SRPX2 in the brain, and suggests that a network of SRPX2-interacting proteins classically involved in the proteolytic remodeling of the extracellular matrix and including uPAR participates in the functioning, in the development and in disorders of the speech cortex.