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Josue Lopez

Mentor: Ernesto Fuentes, Ph.D.
Lab Room: 4-611 BSB
Lab Phone: 319-335-7249

Determining the regulatory mechanisms and identification of inhibitors for the Tiam1/SDC1 interaction

Rac1 is a member of the Rho family GTPase proteins that is important for actin polymerization, microtubule stability, cell polarity and migration. The T-cell lymphoma invasion and metastasis (Tiam1) is a guanine exchange factor (GEF) that regulates Rac1 activation. Deregulation of Tiam1 contributes to epithelial-mesenchymal transition EMT. This regulates cell polarity and adhesion disruption to the epithelial basement membrane allows cellular penetration into the extracellular matrix. EMT is a requirement for tumor cells to become invasive and to metastasize. The molecular mechanisms for how upstream signaling regulates Tiam1-Rac1 activity and how this signaling contributes to EMT are not understood. Previous work in our lab has demonstrated that Tiam1 PDZ domain binds with the transmembrane protein syndecan1 (SDC1). Furthermore, this interaction was shown to be involved in cell-matrix adhesion and cell migration. This protein interaction connects two pathways implicated in cancer previously not described.

The long-term goal of this project is to elucidate the regulation and the physiological role of the Tiam1 PDZ/SDC1 interaction and evaluate its potential target for cancer therapeutics. In the current model, the interaction between SDC1 and Tiam1 PDZ domain promotes local activation of Rac1, resulting in critical cell signaling for cell-cell junctions, cell migration and cell-matrix adhesion. We hypothesize that the Tiam1 PDZ/SDC1 interaction plays a role in invasive cancers and the disruption of the interaction will decrease invasiveness and therefore metastasis. The rationale for this research is to advance knowledge in the regulation of the Tiam1/SDC1 interaction, which is critical for developing novel strategies for cancer therapeutics.