Multiplexed kinase interactome profiling quantifies cellular network activity and plasticity

Golkowski, Martin; Lius, Andrea; Sapre, Tanmay; Lau, Ho-Tak; Moreno, Taylor; Maly, Dustin J.; Ong, Shao En

doi:10.1016/j.molcel.2023.01.015

Cited by 12 publications

(6 citation statements)

References 78 publications

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“…RALBP1 is an effector of Ral GTPase that can interact with the μ2 subunit of AP2 and regulate endocytosis (Jullien-Flores et al, 2000). Importantly, human AAK1 interacted with both RALBP1 and REPS1 in several high-throughput mass spectrometry analyses (Huttlin et al, 2017; Huttlin et al, 2021; Cho et al, 2022; Golkowski et al, 2023). SEL-5 thus could regulate the AP2 complex indirectly via interaction with the REPS1-RALBP1 complex.…”

Section: Discussionmentioning

confidence: 99%

Caenorhabditis elegansSEL-5/AAK1 regulates cell migration and cell outgrowth independently of its kinase activity

Knop

Zounarová

Macůrková

2023

Preprint

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During Caenorhabditis elegans development multiple cells migrate long distances or extend processes to reach their final position and/or attain proper shape. Wnt signalling pathway stands out as one of the major coordinators of cell migration or cell outgrowth along the anterior-posterior body axis. Wnt signalling outcome is fine-tuned by various mechanisms including endocytosis. In this study we show that SEL-5, the C. elegans orthologue of mammalian AP2-associated kinase AAK1, acts together with the retromer complex as a positive regulator of EGL-20/Wnt signalling during the migration of QL neuroblast daughter cells. At the same time, SEL-5 in cooperation with the retromer complex is also required during excretory canal cell outgrowth in a Wnt-independent manner. Importantly, SEL-5 kinase activity is not required for its role in either neuronal migration or excretory cell outgrowth and neither of these processes is dependent on DPY-23/AP2M1 phosphorylation. While Wnt proteins do not significantly contribute to the excretory canal guidance, LIN-44/Wnt and LIN-17/Frizzled together generate a stop signal inhibiting further canal outgrowth.

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Section: Discussionmentioning

confidence: 99%

Caenorhabditis elegansSEL-5/AAK1 regulates cell migration and cell outgrowth independently of its kinase activity

Knop

Zounarová

Macůrková

2023

Preprint

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“…Developments in computational approaches are also likely to be key to unlocking the potential of pharmacological approaches to understand protein kinase signaling networks. Efforts to rationalize the inhibitor libraries used for phenotypic studies, either to create libraries of high selectivity for each target kinase ( Moret et al, 2019 ; Wells et al, 2021 ) or suitable for deconvolution approaches ( Gujral et al, 2014b ; Rata et al, 2020 ; Watson et al, 2020 ; Golkowski et al, 2023 ), will help optimize the trade-off between library size and experimental practicality. Further work should help to determine which algorithms are most effective for identifying relevant kinases and pathways from inhibitor-induced perturbations in the phosphoproteome, for target deconvolution based on phenotypic screens, and for rational design of polypharmacological agents and drug combinations ( Gujral et al, 2014b ; Hernandez-Armenta et al, 2017 ; Tang, 2017 ; Rocca and Kholodenko, 2021 ) Finally, machine learning is poised to provide notable advances in determining features of kinase networks that predict drug efficacy for personalized medicine, as well as in these other areas.…”

Section: Discussionmentioning

confidence: 99%

“…Similar to KiPIK, by correlating the known inhibition fingerprints for kinases with displacement fingerprints of putative kinase-associated proteins determined by mass spectrometry, the “kiCCA” method was able to identify proteins associated with 238 different kinases. In this way, local context-specific kinase PPI networks can be examined ( Golkowski et al, 2023 ).…”

Section: Pharmacological Approaches For Analyzing Kinase Signaling Ne...mentioning

confidence: 99%

“…Importantly, kinases that contribute to such newly discovered signatures, or other regulators such as epigenetic modifiers, may also provide new targets for drug discovery ( Casado et al, 2018 ; Pedicona et al, 2022 ). Drug sensitivity signatures may also be discovered using more targeted approaches such as PamChip (see section 5.4 ) ( Elst et al, 2011 ) or using Kinobeads to enrich for kinases ( Cooper et al, 2013 ; Golkowski et al, 2023 ; 2020 ).…”

Section: Pharmacological Approaches For Analyzing Kinase Signaling Ne...mentioning

confidence: 99%

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Pharmacological approaches to understanding protein kinase signaling networks

Stephenson,

Higgins

2023

Front. Pharmacol.

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Protein kinases play vital roles in controlling cell behavior, and an array of kinase inhibitors are used successfully for treatment of disease. Typical drug development pipelines involve biological studies to validate a protein kinase target, followed by the identification of small molecules that effectively inhibit this target in cells, animal models, and patients. However, it is clear that protein kinases operate within complex signaling networks. These networks increase the resilience of signaling pathways, which can render cells relatively insensitive to inhibition of a single kinase, and provide the potential for pathway rewiring, which can result in resistance to therapy. It is therefore vital to understand the properties of kinase signaling networks in health and disease so that we can design effective multi-targeted drugs or combinations of drugs. Here, we outline how pharmacological and chemo-genetic approaches can contribute to such knowledge, despite the known low selectivity of many kinase inhibitors. We discuss how detailed profiling of target engagement by kinase inhibitors can underpin these studies; how chemical probes can be used to uncover kinase-substrate relationships, and how these tools can be used to gain insight into the configuration and function of kinase signaling networks.

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“…Many past studies, including ours, have demonstrated that protein-protein interactions (PPIs) play a critical role in oncogenic signaling in addition to the role of oncogenic proteins themselves [55,56].…”

Section: Discussionmentioning

confidence: 99%

Quercetin inhibits truncated isoform of dopamine- and cAMP-regulated phosphoprotein as adjuvant treatment for Trastuzumab therapy resistance in HER2-positive breast cancer

Chang,

Cheng,

Liao

et al. 2023

Food Science and Human Wellness

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Trastuzumab resistance is one of the causes of poor prognosis in patients with HER2-positive (HER2+) breast cancer (BC). The truncated isoform of dopamine-and cAMP-regulated phosphoprotein (t-DARPP) has been reported to be involved in Trastuzumab therapy resistance and promoting tumor progression. To evaluate the t-DARPP expression in BC, paired tumors and surrounding normal tissues were analyzed by real-time PCR and confirmed higher DARPP-32 family mRNA expression in HER2+ BC tumor tissues. We established two patient-derived xenografts (PDX) mice models to test the efficacy of Trastuzumab, named model 1 (non-responder) and model 2 (responder). t-DARPP and p95-HER2 protein-protein interactions were detected in PDX tumor tissue from non-responders using Förster resonance energy transfer assays. Instead, there is no response from the responder. Furthermore, mechanistic studies using transwell and western blot assays demonstrated that t-DARPP could upregulate epithelial-mesenchymal transition signaling proteins, enhance p95-HER2 expression and promote cell migration. We found that Quercetin effectively reduced t-DARPP expression in HER2+ BC cells. In t-DARPP ShRNA-suppressed cells, Quercetin synergistically enhanced Trastuzumab-induced apoptotic cell death and G2/M phase arrest. In conclusion, the combination of Quercetin and Trastuzumab treatment by targeting t-DARPP in HER2+ BC patients has the potential as a biomarker for mitigating drug resistance.Keywords：p95-Human Epidermal Growth Factor Receptor 2 (p95-HER2), HER2-positive (HER2+) breast cancer, Quercetin, Trastuzumab resistance, Truncated isoform of dopamine-and cAMP-reg+ulated phosphoprotein (t-DARPP)

show abstract

Multiplexed kinase interactome profiling quantifies cellular network activity and plasticity

Cited by 12 publications

References 78 publications

Caenorhabditis elegansSEL-5/AAK1 regulates cell migration and cell outgrowth independently of its kinase activity

Caenorhabditis elegansSEL-5/AAK1 regulates cell migration and cell outgrowth independently of its kinase activity

Pharmacological approaches to understanding protein kinase signaling networks

Quercetin inhibits truncated isoform of dopamine- and cAMP-regulated phosphoprotein as adjuvant treatment for Trastuzumab therapy resistance in HER2-positive breast cancer

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