New Invasion and Metastasis Molecule, Tiam1 and its Interaction with the Cytoskeleton are Involved in Human Breast Cancer Progression

摘要

In breast tumor cells (e.g., SP1 cells), the guanine nucleotide exchange factor (GEF, the dbl or DR family), Tiam1 (T lymphoma invasion and metastasis) is detected as a 200 kDa protein. Tiam1 is capable of catalyzing GDP/GTP exchange for Rac1. In particular, the aa393-aa738 sequence of Tiam1, which contains the NH2-terminal pleckstrin homology (PHn), a putative coiled coil region (CC) and an additional adjacent region (Ex) (designated as PHn-CC-Ex domain of Tiam1), is involved in the direct interaction with CD44v3 isoform (the hyaluronan receptor) and ankyrin (the cytoskeletal protein) both in vivo and in vitro. Specifically, the binding of HA to the CD44v3 isoform stimulates Tiam1- specific GDP/GTP exchange for Rho-like GTPases such as Rac1, and promotes cytoskeleton-mediated breast tumor cell migration. Furthermore, we have demonstrated that the PHn-CC-Ex domain of Tiam1 contains an ankyrin binding site. The structural homology between the ankyrin binding domain of Tiam1 (the sequence between aa717 and aa727 within the PHn-CC-Ex domain) and CD44 is quite striking. Most importantly, the Tiam1-ankyrin interaction also promotes Rac1 activation and breast tumor cell migration. These observations clearly indicate that Tiam1 contains multiple functional domains (e.g., a CD44-specific membrane localization site and a cytoskeleton binding region for ankyrin) required for the regulation of Tiam1-Rac1 signaling and cytoskeleton function during metastatic breast tumor progression.