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Determination of the Structure and Function of the Breast Cancer Associated Protein (BCA3/AKIP1) and its Interacting Partners.

Michael Kuchinskas

Appointment Period: 2007-2009 / Grant Year: [23,24]

Michael KuchinskasOur laboratory has successfully identified a novel protein that is shown to be upregulated in breast cancer and involved in binding and transport of many key cell cycle and stress related proteins. This breast cancer associated protein (BCA3) was identified as directly interacting with Protein Kinase A (PKA) and termed a-kinase-interacting protein 1 (AKIP1). Further investigation has demonstrated that AKIP1 interacts and shuttles a number of critical cell cycle and apoptotic factors, such as the apoptosis inducing factor, AIF, the cell survival transcription factor, NF-kappaB, and a tumor suppressing splicing kinase, SRPK1. My research is focused on elucidating these interactions via structural analysis of the protein complexes. I have been able to show direct interaction of purified AKIP1 and the N-terminus of the catalytic subunit of PKA and am working toward determining the mechanism of interaction by crystallizing this complex. In addition, I am working on mapping the interaction sites of AIF, NF-kappaB and SRPK1 to aid in the process of structural determination of these complexes. An understanding of how these proteins form a complex with AKIP1 will help determine its role in breast cancer and allow further research into utilizing this protein’s unique shuttling ability to target the disease.

We have successfully expressed AKIP1b. We have also successful expressed some of its binding partners, including AIF. We have mapped the binding sites using peptide arrays, and we now believe we have a solid understanding of where these proteins are binding on AKIP. Others in the lab are defining the biological interactions of AKIP with NF-kappaB, and we are defining the interactions of AKIP with the splicing kinase SRPKI.

Steichen JM, Kuchinskas M, Keshwani MM, Yang J, Adams JA, Taylor SS.Structural basis for the regulation of protein kinase a by activation loopphosphorylation. J Biol Chem. 2012 Apr 27;287(18):14672-80. Epub 2012 Feb 10.PubMed PMID: 22334660.