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- W4313349583 abstract "Abstract Strong NF-κB activation requires ligation of both the CD28 co-receptor and TCR. PDK1 acts as a scaffold by binding both PKCθ and CARMA1 and is therefore essential for signaling to NF-κB . Here, we demonstrate the importance of PDK1 threonine (Thr)-513 phosphorylation in regulating the intermolecular organization of PDK1 homodimers. Thr-513 is directly involved in heterotypic PDK1 homodimer formation, in which binding is mediated through the pleckstrin homology (PH) and kinase domains. Upon activation, phosphorylated Thr-513 instead mediates homotypic intermolecular binding through the PH domains. Consequently, cell permeable peptides with a Thr-513 to Ile derivative (PTD-PDK1-Thr-513-Ile) bound the kinase domain and while a Thr-513 to Asp peptide (PTD-PDK1-Thr-513-Asp) bound the PH domain. PTD-PDK1-Thr-513-Ile blocked binding between PDK1 and PKCθ, phosphorylation of PKCθ Thr-538, and activation of both NF-κB and AKT. In contrast, PTD-PDK1-Thr-513-Asp selectively inhibited binding between PDK1 and CARMA1 and blocked TCR/CD28 induced NF-κB activation. Therefore, Thr-513 phosphorylation regulates a critical intermolecular switch governing PDK1 homodimer structure and the capacity to interact with downstream signaling pathway components. Given the pleiotropic functions of PDK1, these data may open the door to the development of immunosuppressive therapies that selectively target the PDK1 to NF-κB pathway in T cell activation." @default.
- W4313349583 created "2023-01-06" @default.
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- W4313349583 date "2013-05-01" @default.
- W4313349583 modified "2023-09-30" @default.
- W4313349583 title "Transition from heterotypic to homotypic PDK1 homodimerization is essential for TCR-mediated NF-κB activation (P1370)" @default.
- W4313349583 doi "https://doi.org/10.4049/jimmunol.190.supp.203.2" @default.
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