Protein Kinase Regulation and GTPase Signaling

Kinetic Signatures of RAS-BRAF Engagement Reveal Isoform Selectivity, Oncogenic Amplification, and Mutation-Dependent Inhibitor Resistance

This study identifies kinetic differences in RAS-BRAF engagement between KRAS and NRAS, showing how oncogenic mutations and inhibitor sensitivity are influenced by these dynamics.

Structural and Energetic Determinants of Monobody Recognition of Oncogenic KRAS Variants

This study identifies structural and energetic determinants of monobody 12D4 recognition of KRAS variants using simulations and redesign, revealing key interactions and mutations for improved selectivity.

Grb2 Phosphorylation Antagonizes EGFR-driven Ras Activation by Interfering with Condensate Assembly

This study shows that Grb2 phosphorylation at Y160 inhibits EGFR condensate formation, thereby reducing Ras activation, and reveals how kinase inhibition can promote Ras signaling under certain conditions.

RAStoERK: a reference interaction atlas for insights into signaling and disease

The paper creates a comprehensive reference map of the RAS/RAF/MEK/ERK pathway interactomes and their mutation-driven rewiring, revealing new interactions and disease links.

Development of NanoBRET cellular target engagement assays in primary neurons for activating mutants of p21-activated kinase 1

This paper develops NanoBRET assays for PAK1 and its mutant in primary neurons to evaluate inhibitor target engagement.

Targeting Distinct Cell Cycle Nodes Overcomes KRAS/RAS Inhibitor Resistance

This study identifies sustained cell cycle activity as a mechanism of resistance to KRAS inhibitors and shows that co-targeting cell cycle nodes with CDK4/6 or CDK2 restores sensitivity and provides durable tumor control.

Mechanism of activation of an ancestral Tec kinase by PIP3

This study identifies how PIP3 activates an ancestral Tec kinase by displacing its PH domain from an inhibitory interaction with its kinase domain.

PIP5K-Ras bistability triggers plasma membrane symmetry breaking to define cellular polarity and regulate migration

This study identifies a PIP5K-Ras bistable circuit that drives plasma membrane symmetry breaking, leading to cellular polarity and migration.

LAT condensation gates PLCγ1 activation via bimodal LAT phosphorylation

This study shows LAT condensation gates PLCγ1 activation through bimodal LAT phosphorylation, enhancing signal amplification and noise suppression in T cells.

Structure-informed theoretical modeling defines principles governing avidity in bivalent protein interactions

The paper develops a theoretical framework to predict avidity in bivalent protein interactions using structure-informed modeling and experimental validation.

p190A/ARHGAP35 and p190B/ARHGAP5 proteins in endometrial cancer, a novel cancer-relevant paralog interplay

This study identifies a novel paralog interplay between p190A and p190B in endometrial cancer, showing synthetic lethality and actin remodeling effects upon their removal.

Slap restricts oncogenic Src-family kinase signaling to maintain colonic epithelial homeostasis

This study identifies SLAP as a tumor suppressor that limits SFK activity in colonic epithelial cells, preventing tumorigenesis and hyperproliferation.

Endogenous tracking reveals paralog-specific targets for phosphatidic acid generation during phospholipase C signaling in living cells

The paper investigates paralog-specific effects of DGK inhibitors on PA generation during PLC signaling in live cells, finding that BMS-502 inhibits PA production while R59022 paradoxically increases it.

Changes in the Transcriptome and Synthetic Lethal Dependencies Following KRAS Mutant Expression Reveal Profound Tissue-Specificity

This paper identifies tissue-specific synthetic lethal dependencies driven by KRAS mutations across different cell lineages, revealing distinct genetic vulnerabilities shaped by the tissue context.

Phosphorylation Protects Oncogenic RAS from LZTR1-Mediated Degradation

This study identifies phosphorylation as a mechanism protecting oncogenic RAS from LZTR1-mediated degradation, with implications for targeting RAS stability in hematologic cancers.

Molecular determinants of differential substrate selection between the Src family kinases Lck and Src

The paper investigates how Lck and Src kinases differ in their ability to phosphorylate ITAMs, identifying structural and conformational differences that underlie their substrate specificity.

A chemical-genetic approach for stress-independent activation of the fission yeast stress-activated protein kinase pathway

The paper introduces a new yeast strain, SISA4, for sustained Sty1 kinase activation without external stress and demonstrates its utility in studying SAPK pathway effects.

Human TBC1 domain-containing kinase is a class I multidomain pseudokinase

The paper characterizes human TBCK as a class I pseudokinase through biochemical and biophysical analysis, revealing its catalytically inactive nature and structural features.

Small molecule activation of the tumor suppressor kinase LKB1

This study develops small molecules that activate the tumor suppressor kinase LKB1 and shows their therapeutic benefits in cancer cell lines.

Loss of Copine D Leads to Ras Activation in Dictyostelium discoideum

This study shows that loss of Copine D in Dictyostelium discoideum increases Ras activation, leading to developmental and cellular changes similar to those seen in cancer.

How Functional Variants Reconfigure the Rac2 Conformational Landscape

This study investigates how mutations in Rac2 alter its conformational dynamics and signaling, revealing distinct inactive and overactive states that impact cellular function.

PLCβs are recruited to the plasma membrane in macrophages by both Gβγ and Gαq

This study shows that PLCβ3 is recruited to the plasma membrane by both Gβγ and Gq in macrophages, revealing dual mechanisms for G protein-dependent regulation of PLCβ enzymes.

Reconstitution of Ras-PI3Kγ membrane communication and feedback using light-induced signaling inputs

This study reconstitutes Ras-PI3Kγ membrane communication and feedback using light-induced signaling inputs, revealing how feedback and diffusion shape spatiotemporal signaling dynamics.

Divergent CRD-Dependent Mechanisms Govern RAS Isoform-Selective Recruitment of CRAF and ARAF

This study identifies divergent CRD-dependent mechanisms by which RAS isoforms selectively recruit CRAF and ARAF, revealing how the CRD modulates RAS affinity and RAF activation.

Paradoxical non-catalytic kinase functions are driven by inhibitor-induced displacement of autoinhibitory domains

The paper identifies inhibitor-induced structural changes in kinases that drive non-catalytic effects, revealing the ATP-binding site as a key regulator of kinase conformation and interactions.

Magnesium as a Conformational Gatekeeper of KRAS: Structural Dynamics and Therapeutic Implications

This study investigates how magnesium regulates KRAS conformational dynamics and nucleotide exchange using HDX-MS and functional assays, revealing Mg2+ as a critical structural stabilizer.

Nanoclustering and signaling of KRAS G12C and KRAS G12D respond to lipid acyl chain remodeling in an allele-specific manner

This study shows that KRAS G12C and G12D mutants respond differently to lipid acyl chain remodeling, affecting their nanoclustering and signaling activities.

Glutamine Tautomerization Drives RhoGAP-Aided GTP Hydrolysis in Small Rho GTPases

The paper resolves the mechanism of GTP hydrolysis in the RhoGAP-RhoA complex, revealing a tautomerization-driven process involving Gln63.

Long range mutual activation establishes Rho and Rac polarity during cell migration

The paper reveals a long-range mutual activation mechanism between Rho and Rac GTPases that establishes polarity during cell migration, conserved in epithelial cells and essential for T cell migration.

Kinase condensates enrich ATP and trigger autophosphorylation

This study shows kinase condensates enhance autophosphorylation by concentrating kinases and ATP, revealing phase separation as a mechanism to activate kinase signaling.