Bi-directional regulation of chemokine receptor signaling

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PROJECT SUMMARY Cervical cancer remains one of the leading causes of cancer-related deaths world-wide. A large body of evidence indicates that a sub-family of G protein-coupled receptors (GPCRs), known as chemokine receptors, are linked to progression of several cancers, including cervical cancer. Dysregulated signaling of certain chemokine receptors correlates with poor prognosis in cervical cancer, yet the mechanisms remain poorly understood. The overall objective of this proposal is to determine the mechanisms governing chemokine receptor regulation in the context of cervical cancer growth and metastasis. This is significant because these studies will define new targets for clinical potential. Specifically, we will focus on a novel paradigm that governs chemokine receptor bi-directional regulation by A kinase anchoring proteins (AKAPs). AKAPs are scaffolding proteins that bind and nucleate multiple proteins, usually belonging to a common signaling pathway, to spatially and temporally control signaling to drive physiological responses. We performed a siRNA screen of AKAPs expressed in HeLa cells, a cervical cancer cell line, and provide evidence that AKAPs are involved in cross- regulation of chemokine receptor trafficking. Further, using biochemical and biophysical approaches we provide evidence that chemokine receptors reside in a compartment with AKAPs and protein kinas C (PKC), but that other GPCRs are excluded. It is possible that chemokine receptors might co-reside in a sub- compartment at the plasma membrane that enables their cross-regulation without input from other GPCRs, likely to exclusively fine tune their signaling. Based on published and new preliminary data we hypothesize that chemokine receptors are part of a multimeric protein complex compartmentalized by AKAPs that governs their bi-directional regulation. To test this hypothesis we will pursue three specific aims. Aim 1: To determine the role of PKC in bi-directional chemokine receptor regulation; Aim 2: To determine the role of AKAPs in chemokine receptor bi-directional trafficking and signaling; and Aim 3: To determine the role of bi-directional chemokine receptor regulation in cervical cancer in vitro and in vivo. At the conclusion of the proposed studies we expect to determine the mechanism of bi-directional regulation of chemokine receptor signaling. Importantly, we expect to establish that novel aspects of chemokine receptor regulation and signaling could be targeted to treat cervical cancer.