Affiliation: University of California
Alfonso S, Callender J, Hooli B, Antal C, Mullin K, Sherman M, et al
. Gain-of-function mutations in protein kinase CÎ± (PKCÎ±) may promote synaptic defects in Alzheimer's disease. Sci Signal. 2016;9:ra47 pubmed publisher
..In contrast, reduced PKCÎ± activity is implicated in cancer. Hence, these findings reinforce the importance of maintaining a careful balance in the activity of this enzyme. ..
Kajimoto T, Caliman A, Tobias I, Okada T, Pilo C, Van A, et al
. Activation of atypical protein kinase C by sphingosine 1-phosphate revealed by an aPKC-specific activity reporter. Sci Signal. 2019;12: pubmed publisher
..Together, our findings identify a previously undescribed molecular mechanism of aPKC regulation, a molecular target for S1P in cell survival regulation, and a tool to further explore the biochemical and biological functions of aPKC. ..
Baffi T, Van A, Zhao W, Mills G, Newton A. Protein Kinase C Quality Control by Phosphatase PHLPP1 Unveils Loss-of-Function Mechanism in Cancer. Mol Cell. 2019;74:378-392.e5 pubmed publisher
..Thus, PHLPP1 provides a proofreading step that maintains the fidelity of PKC autoinhibition and reveals a prominent loss-of-function mechanism in cancer by suppressing the steady-state levels of PKC. ..
Balasuriya N, Kunkel M, Liu X, Biggar K, Li S, Newton A, et al
. Genetic code expansion and live cell imaging reveal that Thr-308 phosphorylation is irreplaceable and sufficient for Akt1 activity. J Biol Chem. 2018;293:10744-10756 pubmed publisher
..Our data also indicate that pThr-308 should be regarded as the primary diagnostic marker of Akt activity. ..
Callender J, Yang Y, Lordén G, Stephenson N, Jones A, Brognard J, et al
. Protein kinase Cα gain-of-function variant in Alzheimer's disease displays enhanced catalysis by a mechanism that evades down-regulation. Proc Natl Acad Sci U S A. 2018;115:E5497-E5505 pubmed publisher
..Our results unveil how an AD-associated mutation in PKCα permits enhanced agonist-dependent signaling via a mechanism that evades the cell's homeostatic down-regulation of constitutively active PKCα. ..
Kunkel M, Newton A. Protein kinase d inhibitors uncouple phosphorylation from activity by promoting agonist-dependent activation loop phosphorylation. Chem Biol. 2015;22:98-106 pubmed publisher
..These findings illustrate the diverse conformational effects that small molecules exert on their target proteins, underscoring the importance of using caution when interpreting kinase activity from phosphorylation state. ..
Tobias I, Kaulich M, Kim P, Simon N, Jacinto E, Dowdy S, et al
. Protein kinase CÎ¶ exhibits constitutive phosphorylation and phosphatidylinositol-3,4,5-triphosphate-independent regulation. Biochem J. 2016;473:509-23 pubmed publisher
..Rather, we propose that scaffolding near substrates drives the function of PKCÎ¶. ..
Antal C, Hudson A, Kang E, Zanca C, Wirth C, Stephenson N, et al
. Cancer-associated protein kinase C mutations reveal kinase's role as tumor suppressor. Cell. 2015;160:489-502 pubmed publisher
..These data establish that PKC isozymes generally function as tumor suppressors, indicating that therapies should focus on restoring, not inhibiting, PKC activity. ..
Antal C, Callender J, Kornev A, Taylor S, Newton A. Intramolecular C2 Domain-Mediated Autoinhibition of Protein Kinase C Î²II. Cell Rep. 2015;12:1252-60 pubmed publisher
..Although the placement of the C1 domains remains to be determined, elucidation of the structural basis for autoinhibition of PKCÎ²II unveils a unique direction for therapeutically targeting PKC. ..