Biology subjects

Paddock, M. N.

Publications and source records attributed to Paddock, M. N..

4 recordsLinked to original sources

bioRxiv2026

PTPN1/2 inhibits alveolar macrophage-mediated control of lung metastasis

Metastasis remains the leading cause of cancer mortality, yet effective therapies are limited. While therapeutic responses are influenced by organ-specific immune microenvironments, strategies to pharmacologically modulate these niches remain poorly defined. Here, using the clinical-stage inhibitor ABBV-CLS-484 (AC484) as a chemical probe, we demonstrate that systemic PTPN1/2 inhibition remodels the pulmonary myeloid landscape, specifically activating alveolar macrophages (AMs) toward a tumoricidal state. Integrated single-cell/spatial transcriptomics and functional assays reveal that AC484 promotes AM accumulation within metastatic lesions, elevates their IFN{gamma} production and responsiveness, and enhances their tumor-killing activity. Depletion of AMs diminishes the anti-metastatic efficacy of AC484. Mechanistically, inhibiting PTPN1/2 by AC484 amplifies IFN{gamma}-STAT1 signaling in AMs, while disrupting this pathway impairs their tumor control capability. These findings delineate a distinct innate immune axis where PTPN1/2 acts as a molecular "brake" on AM activation, suggesting that pharmacologically unleashing tissue-resident macrophages offers a therapeutic strategy to overcome metastatic progression, particularly in microenvironments where adaptive immunity is insufficient. SignificanceAMs are potent anti-metastatic immune effectors functionally constrained by PTPN1/2. Pharmacologically inhibiting PTPN1/2 amplifies their IFN{gamma}-STAT1 signaling and tumoricidal activity, establishing a strategy to reactivate tissue-resident immunity against metastasis.

immunology↗

bioRxiv2022

Epinephrine inhibits PI3K alpha via the Hippo kinases.

The phosphoinositide 3-kinase, p110, is an essential mediator of insulin signaling and glucose homeostasis. We systematically interrogated the human serine, threonine, and tyrosine kinome to search for novel regulators of p110 and found that the Hippo kinases phosphorylate and completely inhibit its activity. This inhibitory state corresponds to a conformational change of a membrane binding domain on p110, which impairs its ability to engage membranes. In human primary hepatocytes, cancer cell lines, and rodent tissues, activation of the Hippo kinases, MST1/2, using forskolin or epinephrine is associated with phosphorylation and inhibition of p110, impairment of downstream insulin signaling, and suppression of glycolysis and glycogen synthesis. These changes are abrogated when MST1/2 are genetically deleted or inhibited with small molecules. Our study reveals a novel inhibitory pathway of PI3K signaling and a previously unappreciated link between epinephrine and insulin signaling.

physiology↗

bioRxiv2019

Targeting the PI5P4K lipid kinase family in cancer using novel covalent inhibitors

The PI5P4Ks have been demonstrated to be important for cancer cell proliferation and other diseases. However, the therapeutic potential of targeting these kinases is understudied due to a lack of potent, specific small molecules available. Here we present the discovery and characterization of a novel pan-PI5P4K inhibitor, THZ-P1-2, that covalently targets cysteines on a disordered loop in PI5P4K/{beta}/{gamma}. THZ-P1-2 demonstrates cellular on-target engagement with limited off-targets across the kinome. AML/ALL cell lines were sensitive to THZ-P1-2, consistent with PI5P4Ks reported role in leukemogenesis. THZ-P1-2 causes autophagosome clearance defects and upregulation in TFEB nuclear localization and target genes, disrupting autophagy in a covalent-dependent manner and phenocopying the effects of PI5P4K genetic deletion. Our studies demonstrate that PI5P4Ks are tractable targets, with THZ-P1-2 as a useful tool to further interrogate the therapeutic potential of PI5P4K inhibition and inform drug discovery campaigns for these lipid kinases in cancer metabolism and other autophagy-dependent disorders.

cancer biology↗

bioRxiv2018

PIP4Ks Suppress Insulin Signaling Through a Catalytic-Independent Mechanism

Insulin stimulates conversion of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) to phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3), which mediates downstream cellular responses. PI(4,5)P2 is produced by phosphatidylinositol-4-phosphate 5-kinases (PIP5Ks) and byphosphatidylinositol-5-phosphate 4-kinases (PIP4Ks). Here we show that deletion of the three genes that encode PIP4Ks (PIP4K2A, PIP4K2B and PIP4K2C) in vitro results in a paradoxical increase in PI(4,5)P2 and a subsequent increase in insulin-stimulated production of PI(3,4,5)P3. Surprisingly, reintroduction of either wild-type or kinase-dead forms of the PIP4Ks restored cellular PI(4,5)P2 levels and insulin stimulation of the PI3K pathway. These effects are explained by an increase in PIP5K activity upon deletion of PIP4Ks, which we demonstrate can suppress PIP5K activity in vitro through a direct binding interaction. Collectively, our work reveals an important non-catalytic function of PIP4Ks in suppressing PIP5K-mediated PI(4,5)P2 synthesis and insulin-dependent conversion to PI(3,4,5)P3 by PI3K enzymes and suggests that pharmacological depletion of PIP4K enzymes using emerging degrader technologies could represent a novel strategy for stimulating insulin signaling.

cell biology↗