Since this domain spans 84 aa, and in view of the difficulty of synthesizing large peptides, we decided to synthesize a 73 aa peptide spanning aa 25-97, which represents the sequence least similar to the non-interacting AnxA1. In conclusion, the present report demonstrates an extrahepatic physiological function of AnxA2 in regulating PCSK9’s ability to enhance the degradation of the LDLR, especially in adrenals and the digestive organs. Whether AnxA2 is implicated in the fine regulation of PCSK9 function during embryonic development or in some situations requiring high levels of cholesterol, such as in regenerating tissues, will need further studies. The ability of an AnxA2 peptide to inhibit PCSK9 function may be a prelude to the synthesis of novel small molecule inhibitors of PCSK9. The IKK family of kinases consists of four family members, the canonical IKKa and IKKb, as well as two noncanonical family members, IKKe and TBK1. Together, this family of kinases regulates a myriad of critical cellular processes including inflammation, survival, proliferation, senescence, and autophagy. Consistent with these numerous functions, aberrant IKK signaling can result in susceptibility to diseases such as inflammatory disorders and cancer. The canonical IKK complex, which consists of IKKa, IKKb, and a regulatory subunit, NEMO, is a point of convergence for a variety of stimuli. Upon activation, the canonical IKKs, primarily IKKb, phosphorylate IkBa, the inhibitor of NF-kB, which promotes the ubiquitination and degradation of IkBa. The transcription factor NF-kB is then freed to accumulate in the FTY720 nucleus and U0126 109511-58-2 activate the transcription of a number of target genes involved in inflammatory and stress responses. In contrast to the canonical IKKs, IKKe and TBK1 are activated by a smaller subset of inflammatory stimuli, and are especially critical for antiviral responses. These kinases phosphorylate and activate the transcription factors IRF3, IRF7, and STAT1, promoting a Type 1 interferon response. These kinases also activate NF-kB, but the mechanism by which this occurs in unclear since they do not phosphorylate both of the serines on IkBa which are required for IkBa degradation. IKKe and TBK1 can also promote oncogenesis. For example, IKKe is overexpressed in some breast and ovarian cancers, and TBK1 was recently shown to be important for Ras-induced cell transformation. In spite of the important role these kinases play in both inflammatory and oncogenic signaling, few inhibitors have been identified. BX-795, a small molecule inhibitor of 3phosphoinositide-dependent protein kinase 1, inhibits both IKKe and TBK1 at low nanomolar concentrations in vitro. However, BX795 lacks selectivity as 16 out of 76 tested kinases were inhibited by BX-795 in the nM range. It was also recently shown that a series of azabenzimidazole derivatives inhibits these kinases in the low nM range, but 6 of 79 kinases tested using one of these compounds were inhibited in a range within 10-fold of TBK. These results suggest that IKKe and TBK1 are suitable targets for small molecule inhibitor development, but the need for the development of selective inhibitors of IKKe and TBK1 remains. The development of high throughput assays to identify inhibitors of TBK1 and IKKe was hindered until recently by the absence of information regarding the substrate specificities of these enzymes. Peptide substrates for IKKe and TBK1 are frequently based on the IKKb phosphorylation sites in IkBa, even though there is no evidence that all IKK family members phosphorylate the same substrate repertoires. In fact, the recently published phosphorylation motifs for IKKa, IKKb and IKKe suggest that these kinases do have overlapping.