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Conformational Changes in the Carboxyl Tail of Protein Kinase C and Interaction with Pin1

Nicole Kruse

Appointment Period: 2003-2005, Grant Years: [19,20]

Nicole KruseThe regulation of PKC activity is of fundamental importance to cancer biology, and PKC has emerged as an important therapeutic target. The human PIN1 gene encodes an essential nuclear peptidyl-prolyl cis/trans isomerase, which is involved in the regulation of mitosis. Work from other labs has shown that deletion of PIN1 from HeLa cells induces mitotic arrest, whereas overexpression of PIN1 leads to a G2 phase arrest. The potential importance of Pin1 in cancer is also demonstrated by the observation that loss of Pin1 function (in mouse knockouts) leads to a phenotype resembling a cyclin D1-null phenotype. Furthermore, there is a requirement of Pin1 for the replication checkpoint to function, which is of major importance in allowing proper repair of DNA lesions prior to replication.

Pin1 has been shown to interact with the C-terminal domain of PKC. Importantly, which residues are the main determinants for interaction with Pin1? Why are we seeing isomerization at Pro637 instead of Pro642? In addition to this providing more information about PKC, this will be the first structure of Pin1 with a substrate longer than 5 residues and may provide information about the communication between domains of Pin1. Further experiments will examine the effects of the isomerization on the catalytic activity and biological signaling of PKC. This work leads will thus lead to a greater understanding of these two enzymes, PKC and Pin1, which are both known to play important roles in cell regulation and tumor promotion. My work has discovered Pin1 as a new interaction partner for PKC, and demonstrates that both the phosphorylation sites and proline cis-trans isomerization states act as regulatory to regulate the activity of PKC.

Abrahamsen H, O'Neill AK, Kannan N, Kruse N, Taylor SS, Jennings PA, NewtonAC. Peptidyl-prolyl Isomerase Pin1 Controls Down-regulation of ConventionalProtein Kinase C Isozymes. J Biol Chem. 2012 Apr 13;287(16):13262-78. Epub 2012Feb 8. PubMed PMID: 22318721.