Leukocyte migration is controlled by a leading-edge chemosensory pathway that generates the regulatory lipid phosphatidylinositol-3,4,5-trisphosphate (PIP), a growth signal, thereby driving leading-edge expansion up attractant gradients toward sites of infection, inflammation, or tissue damage. PIP also serves as an important growth signal in growing cells and oncogenesis. The kinases PDK1, AKT1 or PKB, and PKCα are key components of a plasma-membrane-based PIP and Ca signaling circuit that regulates these processes. PDK1 and AKT1 are recruited to the membrane by PIP, whereas PKCα is recruited to the membrane by Ca. All three of these master kinases phosphoregulate an array of protein targets. For example, PDK1 activates AKT1, PKCα, and other AGC kinases by phosphorylation at key sites. PDK1 is believed to form PDK1-AKT1 and PDK1-PKCα heterodimers stabilized by a PDK1-interacting fragment (PIF) interaction between the PDK1 PIF pocket and the PIF motif of the AGC binding partner. Here, we present the first, to our knowledge, single-molecule studies of full-length PDK1 and AKT1 on target membrane surfaces, as well as their interaction with full-length PKCα. These studies directly detect membrane-bound PDK1-AKT1 and PDK1-PKCα heterodimers stabilized by PIF interactions formed at physiological ligand concentrations. PKCα exhibits eightfold higher PDK1 affinity than AKT1 and can competitively displace AKT1 from PDK1-AKT1 heterodimers. Ensemble activity measurements under matched conditions reveal that PDK1 activates AKT1 via a cis mechanism by phosphorylating an AKT1 molecule in the same PDK1-AKT1 heterodimer, whereas PKCα acts as a competitive inhibitor of this phosphoactivation reaction by displacing AKT1 from PDK1. Overall, the findings provide insights into the binding and regulatory interactions of the three master kinases on their target membrane and suggest that a recently described tumor suppressor activity of PKC isoforms may arise from its ability to downregulate PDK1-AKT1 phosphoactivation in the PIP-PDK1-AKT1-mTOR pathway linked to cell growth and oncogenesis.
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http://dx.doi.org/10.1016/j.bpj.2021.10.015 | DOI Listing |
Cell Commun Signal
December 2024
College of Life Science, Northwest A&F University, Yangling, Shaanxi, 712100, P.R. China.
Timely and accurate translation of maternal mRNA is essential for oocyte maturation and early embryonic development. Previous studies have highlighted the importance of Primordial Germ cell 7 (PGC7) as a maternal factor in maintaining DNA methylation of maternally imprinted loci in zygotes. However, it is still unknown whether PGC7 is involved in the regulation of Maternal mRNA Translation.
View Article and Find Full Text PDFPsychiatry Res
November 2024
The Molecular Psychiatry Laboratory, The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.
Cell Insight
August 2024
State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, TaiKang Center for Life and Medical Sciences, TaiKang Medical School, Wuhan University, Wuhan, China.
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide and presents a significant threat to human health. Despite its prevalence, the underlying regulatory mechanisms of HCC remain unclear. In this study, we integrated RNA-seq datasets, proteome dataset and survival analysis and unveiled Stratifin (SFN) as a potential prognostic biomarker for HCC.
View Article and Find Full Text PDFComp Biochem Physiol C Toxicol Pharmacol
September 2024
School of Biological Engineering, Huainan Normal University, Huainan 232038, China.
Diesel particulate extract (DPE), which is a significant constituent of airborne particle pollution, has a strong association with the development of cancer and respiratory diseases. Fulvic acid (FA), a plentiful organic macromolecule found in water, has the capability to modify particle surface charge and adsorption capacity when combined with minerals. Nevertheless, there is a scarcity of data regarding the influence of their interaction on DPE toxicity.
View Article and Find Full Text PDFArch Gerontol Geriatr
October 2024
Department of Applied Chemistry, Dong-Eui University, Busan 614-714, Republic of Korea. Electronic address:
Background: The IGF-1 signaling pathway has been deeply involved in the aging mechanism. The insulin-like growth factor binding protein 3 (IGFBP-3) is a protein that binds to IGF-1 that regulates growth, survival, and aging.
Objective: The purpose of this study was to investigate the impact of the IGFBP3 gene knockout (KO) on the expressions of aging-related proteins and genes using the CRISPR/Cas9 system.
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