ArticleCurrent biology : CB2008
PIP3-independent activation of TorC2 and PKB at the cell's leading edge mediates chemotaxis.
Article in Current biology : CB, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 117 papers.
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117 citing papers in PubMed, 182 citations in OpenAlex.
- Long-range mutual activation establishes Rho and Rac polarity during cell migration.Nature cell biology · 2026Article
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- Redefining the role of IL-18 in post-surgical recovery and sepsis: a key mediator of inflammation resolution.Journal of translational medicine · 2025Article
- Cross-Species Applications of Peptide Substrate Reporters to Quantitative Measurements of Kinase Activity.ACS measurement science au · 2024Article
- Activation of the cell wall integrity pathway negatively regulates TORC2-Ypk1/2 signaling through blocking eisosome disassembly in Saccharomyces cerevisiae.Communications biology · 2024Article
- CRISPR-mediated reversion of oncogenic KRAS mutation results in increased proliferation and reveals independent roles of Ras and mTORC2 in the migration of A549 lung cancer cells.Molecular biology of the cell · 2023Article
- A dynamic partitioning mechanism polarizes membrane protein distribution.Nature communications · 2023Article
- Whole-genome screens reveal regulators of differentiation state and context-dependent migration in human neutrophils.Nature communications · 2023Article
- Mechanosensitive mTORC2 independently coordinates leading and trailing edge polarity programs during neutrophil migration.Molecular biology of the cell · 2023Article
- Ras-mediated activation of mTORC2 promotes breast epithelial cell migration and invasion.Molecular biology of the cell · 2023Article
- Dynamics of Actin Cytoskeleton and Their Signaling Pathways during Cellular Wound Repair.Cells · 2022Article
- Spatiotemporal dynamics of membrane surface charge regulates cell polarity and migration.Nature cell biology · 2022Article
- AKT and SGK kinases regulate cell migration by altering Scar/WAVE complex activation and Arp2/3 complex recruitment.Frontiers in molecular biosciences · 2022Article
- Exercise increases phosphorylation of the putative mTORC2 activity readout NDRG1 in human skeletal muscle.American journal of physiology. Endocrinology and metabolism · 2022Article
- Gradients of PI(4,5)PFrontiers in cell and developmental biology · 2022Article
- C2GAP2 is a common regulator of Ras signaling for chemotaxis, phagocytosis, and macropinocytosis.Frontiers in immunology · 2022Article
- The Amoebal Model for Macropinocytosis.Sub-cellular biochemistry · 2022Article
- Decanoic Acid Stimulates Autophagy inCells · 2021Article
- Leep1 interacts with PIP3 and the Scar/WAVE complex to regulate cell migration and macropinocytosis.The Journal of cell biology · 2021Article
57 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 4 institutions in 3 countries.
Funding
Abstract
backgroundStudies show that high phosphotidylinositol 3,4,5-trisphosphate (PIP(3)) promotes cytoskeletal rearrangements and alters cell motility and chemotaxis, possibly through activation of protein kinase Bs (PKBs). However, chemotaxis can still occur in the absence of PIP(3), and the identities of the PIP(3)-independent pathways remain unknown.
resultsHere, we outline a PIP(3)-independent pathway linking temporal and spatial activation of PKBs by Tor complex 2 (TorC2) to the chemotactic response. Within seconds of stimulating Dictyostelium cells with chemoattractant, two PKB homologs, PKBA and PKBR1, mediate transient phosphorylation of at least eight proteins, including Talin, PI4P 5-kinase, two Ras GEFs, and a RhoGap. Surprisingly, all of the substrates are phosphorylated with normal kinetics in cells lacking PI 3-kinase activity. Cells deficient in TorC2 or PKB activity show reduced phosphorylation of the endogenous substrates and are impaired in chemotaxis. The PKBs are activated through phosphorylation of their hydrophobic motifs via TorC2 and subsequent phosphorylation of their activation loops. These chemoattractant-inducible events are restricted to the cell's leading edge even in the absence of PIP(3). Activation of TorC2 depends on heterotrimeric G protein function and intermediate G proteins, including Ras GTPases.
conclusionsThe data lead to a model where cytosolic TorC2, encountering locally activated small G protein(s) at the leading edge of the cell, becomes activated and phosphorylates PKBs. These in turn phosphorylate a series of signaling and cytoskeletal proteins, thereby regulating directed migration.
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