Jeremy S. Logue
University of Washington
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Featured researches published by Jeremy S. Logue.
Genes & Development | 2012
Jeremy S. Logue; Deborah K. Morrison
Cancer often arises when normal cellular growth goes awry due to defects in critical signal transduction pathways. A growing number of inhibitors that target specific components of these pathways are in clinical use, but the success of these agents has been limited by the resistance to inhibitor therapy that ultimately develops. Studies have now shown that cancer cells respond to chronic drug treatment by adapting their signaling circuitry, taking advantage of pathway redundancy and routes of feedback and cross-talk to maintain their function. This review focuses on the compensatory signaling mechanisms highlighted by the use of targeted inhibitors in cancer therapy.
FEBS Journal | 2010
Jeremy S. Logue; John D. Scott
A fundamental role for protein–protein interactions in the organization of signal transduction pathways is evident. Anchoring, scaffolding and adapter proteins function to enhance the precision and directionality of these signaling events by bringing enzymes together. The cAMP signaling pathway is organized by A‐kinase anchoring proteins. This family of proteins assembles enzyme complexes containing the cAMP‐dependent protein kinase, phosphoprotein phosphatases, phosphodiesterases and other signaling effectors to optimize cellular responses to cAMP and other second messengers. Selected A‐kinase anchoring protein signaling complexes are highlighted in this minireview.
eLife | 2015
Jeremy S. Logue; Alexander X. Cartagena-Rivera; Michelle A. Baird; Michael W. Davidson; Richard S. Chadwick; Clare M. Waterman
Within the confines of tissues, cancer cells can use blebs to migrate. Eps8 is an actin bundling and capping protein whose capping activity is inhibited by Erk, a key MAP kinase that is activated by oncogenic signaling. We tested the hypothesis that Eps8 acts as an Erk effector to modulate actin cortex mechanics and thereby mediate bleb-based migration of cancer cells. Cells confined in a non-adhesive environment migrate in the direction of a very large ‘leader bleb.’ Eps8 bundling activity promotes cortex tension and intracellular pressure to drive leader bleb formation. Eps8 capping and bundling activities act antagonistically to organize actin within leader blebs, and Erk mediates this effect. An Erk biosensor reveals concentrated kinase activity within leader blebs. Bleb contents are trapped by the narrow neck that separates the leader bleb from the cell body. Thus, Erk activity promotes actin bundling by Eps8 to enhance cortex tension and drive the bleb-based migration of cancer cells under non-adhesive confinement. DOI: http://dx.doi.org/10.7554/eLife.08314.001
Journal of Biological Chemistry | 2011
Jeremy S. Logue; Jennifer L. Whiting; Brian Tunquist; Lorene K. Langeberg; John D. Scott
Protein kinase A-anchoring proteins (AKAPs) influence fundamental cellular processes by directing the cAMP-dependent protein kinase (PKA) toward its intended substrates. In this report we describe the identification and characterization of a ternary complex of AKAP220, the PKA holoenzyme, and the IQ domain GTPase-activating protein 2 isoform (IQGAP2) that is enriched at cortical regions of the cell. Formation of an IQGAP2-AKAP220 core complex initiates a subsequent phase of protein recruitment that includes the small GTPase Rac. Biochemical and molecular biology approaches reveal that PKA phosphorylation of Thr-716 on IQGAP2 enhances association with the active form of the Rac GTPase. Cell-based experiments indicate that overexpression of an IQGAP2 phosphomimetic mutant (IQGAP2 T716D) enhances the formation of actin-rich membrane ruffles at the periphery of HEK 293 cells. In contrast, expression of a nonphosphorylatable IQGAP2 T716A mutant or gene silencing of AKAP220 suppresses formation of membrane ruffles. These findings imply that IQGAP2 and AKAP220 act synergistically to sustain PKA-mediated recruitment of effectors such as Rac GTPases that impact the actin cytoskeleton.
Journal of Biological Chemistry | 2011
Jeremy S. Logue; Jennifer L. Whiting; Brian Tunquist; David B. Sacks; Lorene K. Langeberg; Linda Wordeman; John D. Scott
Background: AKAP220 organizes the signaling enzymes PKA, GSK-3, and phosphoprotein phosphatase PP1. Results: AKAP220 interacts with the scaffolding protein IQGAP1 to assimilate and process calcium and cAMP signals at leading edges of migrating cells. Conclusion: AKAP220/IQGAP1 networks position calcium and cAMP-responsive signaling enzymes near substrates at the +TIPs of growing microtubules. Significance: Anchored kinase/microtubule effector protein networks propagate cell motility. Cell movement requires the coordinated reception, integration, and processing of intracellular signals. We have discovered that the protein kinase A anchoring protein AKAP220 interacts with the cytoskeletal scaffolding protein IQGAP1 to influence cell motility. AKAP220/IQGAP1 networks receive and integrate calcium and cAMP second messenger signals and position signaling enzymes near their intended substrates at leading edges of migrating cells. IQGAP1 supports calcium/calmodulin-dependent association of factors that modulate microtubule dynamics. AKAP220 suppresses GSK-3β and positions this kinase to allow recruitment of the plus-end microtubule tracking protein CLASP2. Gene silencing of AKAP220 alters the rate of microtubule polymerization and the lateral tracking of growing microtubules and retards cell migration in metastatic human cancer cells. This reveals an unappreciated role for this anchored kinase/microtubule effector protein network in the propagation of cell motility.
Biophysical Journal | 2016
Alexander X. Cartagena-Rivera; Jeremy S. Logue; Clare M. Waterman; Richard S. Chadwick
The organization of filamentous actin and myosin II molecular motor contractility is known to modify the mechanical properties of the cell cortical actomyosin cytoskeleton. Here we describe a novel method, to our knowledge, for using force spectroscopy approach curves with tipless cantilevers to determine the actomyosin cortical tension, elastic modulus, and intracellular pressure of nonadherent cells. We validated the method by measuring the surface tension of water in oil microdrops deposited on a glass surface. We extracted an average tension of T ∼ 20.25 nN/μm, which agrees with macroscopic experimental methods. We then measured cortical mechanical properties in nonadherent human foreskin fibroblasts and THP-1 human monocytes before and after pharmacological perturbations of actomyosin activity. Our results show that myosin II activity and actin polymerization increase cortex tension and intracellular pressure, whereas branched actin networks decreased them. Interestingly, myosin II activity stiffens the cortex and branched actin networks soften it, but actin polymerization has no effect on cortex stiffness. Our method is capable of detecting changes in cell mechanical properties in response to perturbations of the cytoskeleton, allowing characterization with physically relevant parameters. Altogether, this simple method should be of broad application for deciphering the molecular regulation of cell cortical mechanical properties.
Small GTPases | 2011
Jeremy S. Logue; Jennifer L. Whiting; John D. Scott
Rac GTPases promote formation of membrane ruffles, yet how key effectors of this small GTPase operate in response to intracellular signals is not well established. In our recent report, “Anchored PKA recruitment of active Rac,” we identify a cortical actin cytoskeletal signaling complex containing an A-Kinase Anchoring Protein (AKAP) and the IQGAP2 isoform. We show that dynamic assembly of this complex requires the combined action of calcium and cAMP signals. Furthermore, phosphorylation of IQGAP2 by the AKAP220-anchored PKA enhances Rac binding and membrane ruffling. We also discuss our recent findings and provide additional evidence that phosphorylation of IQGAP2 brings IQGAP2 to membrane ruffles.
Oncogene | 2018
Jeremy S. Logue; Alexander X. Cartagena-Rivera; Richard S. Chadwick
Cancer cell migration requires that cells respond and adapt to their surroundings. In the absence of extracellular matrix cues, cancer cells will undergo a mesenchymal to ameboid transition, whereas a highly confining space will trigger a switch to “leader bleb-based” migration. To identify oncogenic signaling pathways mediating these transitions, we undertook a targeted screen using clinically useful inhibitors. Elevated Src activity was found to change actin and focal adhesion dynamics, whereas inhibiting Src triggered focal adhesion disassembly and blebbing. On non-adherent substrates and in collagen matrices, amoeboid-like, blebbing cells having high Src activity formed protrusions of the plasma membrane. To evaluate the role of Src in confined cells, we use a novel approach that places cells under a slab of polydimethylsiloxane (PDMS), which is held at a defined height. Using this method, we find that leader bleb-based migration is resistant to Src inhibition. High Src activity was found to markedly change the architecture of cortical actomyosin, reduce cell mechanical properties, and the percentage of cells that undergo leader bleb-based migration. Thus, Src is a signal transducer that can potently influence transitions between migration modes with implications for the rational development of metastasis inhibitors.
Proceedings of the National Academy of Sciences of the United States of America | 2005
Blaine H. M. Mooers; Jeremy S. Logue; J. Andrew Berglund
The FASEB Journal | 2009
Jeremy S. Logue; John D. Scott