Effect of Akt1 phosphorylation on RhoC GTPase activity in inflammatory breast cancer
Date
2012
Authors
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Journal ISSN
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Publisher
University of Delaware
Abstract
Inflammatory breast cancer (IBC) is the most highly aggressive and lethal form of breast cancer. It is characterized by primary skin changes that include redness of skin, edema and peau d’ aurange [skin of an orange]. IBC is clinically distinguished by the rapid progression of these symptoms and it has a distinct pathology with tumor emboli that invade and block the dermal lymphatics of the skin over the breast. In the United States, 10-year disease-free survival rates are only 20% due to the aggressiveness and rapid metastasis of IBC.Therefore, it is important to understand the mechanism of metastasis of IBC. A key player that is an important contributor to the IBC metastatic phenotype is RhoC GTPase. RhoC GTPase is a member of Ras-superfamily, which is over-expressed in inflammatory breast cancer and is essential for its metastasis. It acts as a molecular switch, which cycles between a GTP-bound (“on”) state and GDP-bound (“off”) state. Regulation of RhoC GTPase activity occurs through its` interactions with GTPase-activation proteins (GAPs), GDP-dissociation inhibitors (GDIs), and guanine nucleotide exchange factors (GEFs). Previously, our laboratory demonstrated that RhoC is a substrate for Akt1 and its phosphorylation is required for the IBC metastatic phenotype. In addition to the regulation with upstream regulatory proteins, our laboratory has shown that phosphorylation of RhoC by Akt1 affects cell invasion. This project examines whether phosphorylation of RhoC by Akt1 alters the activation state of RhoC or its interaction with regulators of the GTPase cycle.