Alan Hammer

Breast cancer is one of the leading causes of cancer-related deaths in females and the mortality rate of breast cancer increases upon tumor metastasis. Breast cancer cells synthesize and locally secrete the hormone prolactin (PRL) and express high levels of the PRL receptor (PRL-R). Additionally, metastatic breast tumors have increased activity of the serine/threonine kinase PAK1. Importantly, PRL can mediate PAK1 activity through the non-receptor tyrosine kinase JAK2. JAK2 can phosphorylate PAK1 on three tyrosines, Y153, Y201, and Y285, however the role for PAK1 tyrosyl phosphorylation (pTyr-PAK1) is still under investigation. My project aims to determine the role of pTyr-PAK1 in breast cancer cell adhesion, metastasis, and epithelial-to-mesenchymal transition (EMT). Currently we have determined that pTyr-PAK1 has both increased kinase activity and protein/protein binding capabilities. Also, pTyr-PAK1 binds to a complex of proteins including GIT1 and PIX proteins in response to PRL, subsequently localizing pTyr-PAK1 to cell/matrix adhesions and inducing adhesion turnover, a process necessary for cell migration and invasion. The GIT1/PIX/PAK1 complex also localizes to cell/cell junctions and PAK1 is involved in the destabilization of these junctions during EMT. The future goals of this project are to determine how pTyr-PAK1 is involved in regulating cell/cell adhesion and the transition of breast epithelial cells into motile mesenchymal cells.