Science AI Journal
Biochemistry, Genetics and Molecular Biology · Research topic

Open research questions in Protein Kinase Regulation and GTPase Signaling

32 unresolved questions extracted from the limitations and future-work sections of 110 Protein Kinase Regulation and GTPase Signaling papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • ARHGAP20 is a RhoA-specific GAP, a downstream target of the Ras-related GTPase Rap1, and has been implicated in cancer cell motility, yet its functional role in coordinating migration-associated signaling remains poorly understood.

    ARHGAP20 organizes spatial Rap1-RhoA signaling coordination controlling adhesion dynamics during migration · 2026 · DOI

  • In addition to drug- induced EGFR mutations, EGFR-independent mecha- nisms, in resistance-associated signaling networks [20], has been proposed as significant contributors, though their impacts on tumor defense remain unclear.

    Unmasking the common enemy: drug resistance mechanisms across three different EGFR inhibitor generations are associated with co-targetable alterations in extracellular matrix signaling · 2026 · DOI

  • Despite the role of cytoskeletal dysregulation in cancer, the pan-cancer clinical, immunogenomic, and druggability landscape of TUBG1 remains poorly defined.

    Pan-Cancer Multi-Omics and Structure-Guided Drug Discovery Identify TUBG1 as a Clinically and Immunologically Relevant Target · 2026 · DOI

  • Monobody 12D4 exhibits high affinity and selectivity for the oncogenic KRAS(G12D) mutant, but the molecular determinants governing its recognition and the basis for its mutant selectivity remain poorly understood.

    Structural and Energetic Determinants of Monobody Recognition of Oncogenic KRAS Variants · 2026 · DOI

  • The molecular mechanism by which IKK becomes catalytically active in response to signaling remains unclear despite structural knowledge of the individual IKK1/, IKK2/{beta}, and NEMO/IKK{gamma} protein components within its hetero-oligomeric assembly.

    Cryo-EM reveals alternative modes of dimerization driving activation of IKK · 2026 · DOI

  • However, localization of the specific PKA subunits, as well as other signalling proteins involved in this pathway, still need to be explored comprehensively.

    Expression of protein kinase A catalytic subunits in healthy and diseased mouse kidneys · 2026 · DOI

  • While certain multivalent interactions have been shown to be necessary in immune receptor recruitment of partners, bivalent recruitment of tandem SH2 domains more broadly is poorly understood.

    Structure-informed theoretical modeling defines principles governing avidity in bivalent protein interactions · 2026 · DOI

  • A notable design feature of NCT05578092 is the requirement for baseline and on-treatment tumor biopsies for pharmacodynamic evaluation when medically feasible, supporting a rigorous linkage between drug exposure and pathway modulation in humans (Dillon et al., 2021; Sudhakar et al., 2024).

    Disrupting the KRAS–SOS1 protein–protein interaction: mechanistic rationale for pan-KRAS pathway suppression and combination therapy · 2026 · DOI

  • Publicly available efficacy reporting for BI-1701963 remains limited. A snapshot analysis of the BI-1701963 dose-escalation experience in KRAS-mutant solid tumors has been presented at ESMO 2021 (abstract 524P) (Johnson et al., 2021), and additional 'trial in process' updates describing combination cohorts have been disseminated through meeting abstracts (Hofmann et al., 2021).

    Disrupting the KRAS–SOS1 protein–protein interaction: mechanistic rationale for pan-KRAS pathway suppression and combination therapy · 2026 · DOI

  • Mechanistically grounded biomarkers for SOS1 inhibitors are likely to fall into two buckets: (i) markers of upstream dependence where KRAS output remains coupled to RTK–GRB2–SOS signaling, and (ii) markers of pre-existing or readily inducible bypass circuits. Current evidence supports the following practical hypotheses: Higher likelihood of benefit: RTK-high states (strong phospho-RTK contexts with prominent ERK rebound signatures under MAPK-targeted therapy, and settings where preclinical co-targeting data show clear vertical synergy (e.g., KRASG12C plus SOS1; EGFR-mutant spheroid models) (Amodio et al., 2020; Thatikonda et al., 2024; Theard et al., 2020).

    Disrupting the KRAS–SOS1 protein–protein interaction: mechanistic rationale for pan-KRAS pathway suppression and combination therapy · 2026 · DOI

  • Studies show that matrix stiffness modulates tip cell formation through the p-PXN-Rac1-YAP axis and that KIF13A regulates RhoB plasma membrane localization for blebby migration, but how mechanotransduction pathways intersect with Rho GTPase signaling networks to coordinate different migration modes (mesenchymal versus amoeboid) across varying tissue stiffness ranges has not been quantitatively modeled.

    Decoding Rho GTPase signalling networks in directed cell migration · 2026 · DOI

  • The regulation of LARG/ARHGEF12 in leukemia and ARHGEF15 overexpression in pancreatic cancer show enhanced cell motility, but direct comparison of how different GEF families (ARHGEF, DBL, TIAM families) compete for or collaborate in activating Rho GTPases during invasion specifically in three-dimensional extracellular matrix environments has not been systematically investigated.

    Decoding Rho GTPase signalling networks in directed cell migration · 2026 · DOI

  • Multiple papers report that RhoG regulates Rac1-dependent migration through Dock4 and that RhoJ integrates attractive and repulsive cues in endothelial cells, yet the molecular basis for selective activation of specific Rho GTPase family members in response to identical migratory stimuli across different cell types remains poorly defined.

    Decoding Rho GTPase signalling networks in directed cell migration · 2026 · DOI

  • The integration of chemical gradient sensing with Rho GTPase signaling networks for cell polarity orientation has been studied in isolated systems, but the quantitative relationship between chemoattractant concentration gradients and the threshold activation levels of RhoA versus Rac1 needed to maintain directional migration in varying gradient steepnesses remains uncharacterized.

    Decoding Rho GTPase signalling networks in directed cell migration · 2026 · DOI

  • While multiple studies demonstrate that ubiquitination of IQGAP1 diminishes Cdc42 activation and that various phosphorylation events on GEFs like SOS1 modulate GTPase activity, the complete proteomic landscape of post-translational modifications regulating individual Rho family GTPases across different cell types and migration contexts has not been systematically mapped.

    Decoding Rho GTPase signalling networks in directed cell migration · 2026 · DOI

  • The spatio-temporal dynamics of Rho GTPase signaling patterns have been characterized descriptively, but quantitative mathematical models integrating the timing and spatial localization of RhoA, Rac1, and Cdc42 activation during directed migration remain underdeveloped. This gap prevents predictive modeling of how GTPase oscillations control leading and trailing edge dynamics.

    Decoding Rho GTPase signalling networks in directed cell migration · 2026 · DOI

  • The concept of targeting mutant oncoproteins with drugs that distinguish between these proteins and their normal counterparts has been discussed since the early eighties, when HRAS oncogenes were first identified in human tumor DNA. As a proof of concept, we developed antibodies that recognize G12S or G12R specifically, and showed that microinjection of these antibodies into cells transformed by these oncoproteins reverted to a normal phenotype (Feramisco et al. 1985). While this result seems obvious in hindsight, the possibility that oncogenes act in a hit-and-run mode was actively debated (Felsher and Bishop 1999). However, inspection of Fred’s first RAS structure in 1989, and his analysis of nucleotide binding properties, made it obvious that finding drugs that bind to RAS proteins would be extremely difficult, let alone drugs that bind selectively to oncogenic variants. Nevertheless, these drugs have indeed be developed, at least for KRAS mutants, and are in active clinical trials. The first approval for such a drug, the G12C specific sotorasib, was granted in 2021. There are currently at least 50 KRAS inhibitors in clinical trials, with varying degrees of selectivity for KRAS G12C, G12D or G12V, with many more to follow (Ebright et al. 2025). These drugs will certainly bring hope and benefit to patients suffering from pancreatic cancer, lung adenocarcinoma and colorectal cancers with KRAS mutations. Many of these drugs are already being tested in combination therapies, and one combination, adagrasib plus cetuximab, was approved in 2024 for patients suffering from KRAS G12C mutant colorectal cancers. Multiple mechanisms of resistance will inevitably emerge, some of which can be addressed, others, such as resistance caused by state changes in treated cells, will require more research and a better understanding of cancer biology. Drugs that target mutant KRAS without affecting wild type KRAS, should have no side effects. If so, we have an opportunity for the first time in medical oncology, to use potent anti-cancer to prevent cancer rather than treating it. Theoretically, healthy individuals of, say, 60 years of age, could take these medicines and eradicate early KRAS mutant clones and prevent or delay development of KRAS-driven disease. Pan-KRAS drugs that inhibit mutant alleles but also inhibit wild type KRAS may also be safe enough to use in a prevention setting. This is because KRAS appears to be largely dispensable in adult animals, presumably because NRAS and HRAS can compensate following KRAS ablation (Zamorano-Dominguez et al. 2025). Pan-KRAS drugs are currently being tested and should give a clear indication as to whether compensation occurs in humans. RAS biology and drug development has been a long journey, starting with the identification of the HRAS retrovirus v-Ha-Ras, in 1964 by Jennifer Harvey (Harvey 1964), through the re-discovery of HRAS as an oncogene in human tumor DNA, to the current era of molecular and structural analysis of recombinant RAS proteins, alone or in complexes with regulators and effectors. Fred Wittinghofer’s analysis launched and sustained the third of these waves, the one that eventually led to successful development of effective drugs. It has been a pleasure working with him and the other members of the RAS community of which he has been seminal figure and friend on this long journey. Research ethics: Not applicable. Informed consent: Not applicable. Author contributions: The author has accepted responsibility for the entire content of the manuscript and approved its submission. Use of Large Language Models, AI and Machine Learning Tools: None. Conflict of interest: The author is on the Board of Directors of BridgeBio Oncology and an Advisor to Quanta Therapeutics. Research funding: None. Data availability: Not applicable. F.

    The heart of the matter: a personal view of Fred Wittinghofer’s contributions to RAS biology and drug design · 2026 · DOI

  • The comparative analysis between KRAS4a and KRAS4b splice variants in terms of cryptic pocket accessibility and ligandability has not been fully explored; structural and functional distinctions of inhibitor binding between these splice isoforms require detailed investigation.

    Disulfide tethering reveals cryptic pockets in oncogenic KRAS · 2026 · DOI

  • The interaction kinetics between small-molecule ligands and the identified cryptic KRAS pockets, particularly in the context of RAF1 RAS-binding domain engagement and cellular effector recruitment, have not been characterized using kinetic binding assays or cellular engagement studies.

    Disulfide tethering reveals cryptic pockets in oncogenic KRAS · 2026 · DOI

  • While fragment-based drug discovery approaches identified weak binding interactions in KRAS pockets, the methodological gap exists in translating these fragment hits into high-affinity bivalent or multivalent inhibitor designs; structure-activity relationship optimization pathways for pan-RAS inhibition remain to be systematically explored.

    Disulfide tethering reveals cryptic pockets in oncogenic KRAS · 2026 · DOI

  • The paper identifies Switch-II pocket inhibitors but does not comprehensively evaluate their selectivity between active GTP-bound and inactive GDP-bound KRAS conformational states; differential binding affinity measurements for these two nucleotide states across multiple ligand scaffolds remain incomplete.

    Disulfide tethering reveals cryptic pockets in oncogenic KRAS · 2026 · DOI

  • The disulfide tethering approach for identifying cryptic pockets in KRAS has been demonstrated, but the structural characterization of ligand-binding constraints specific to KRAS G12C, G12V, and G12S alleles requires systematic comparative structural analysis to determine allele-specific binding selectivity differences.

    Disulfide tethering reveals cryptic pockets in oncogenic KRAS · 2026 · DOI

  • Although other genetic features, such as KRAS gene copy number variations (CNV) and mutant allele fractions (MAF), have been observed, their influence on response to treatment remains unclear.

    Abstract B032: KRAS copy number variation and mutant allele fractions predict in vitro response of PDX-derived human pancreatic cancer cell lines to KRASG12D inhibitor MRTX1133 · 2023 · DOI

  • Although there are numerous investigations of the role played by ras genes in the de- velopment of insects, this problem is still not fully understood.

    Universal intracellular transducer ras and its role in the development of drosophila · 2013 · DOI

Most-cited papers in Protein Kinase Regulation and GTPase Signaling

Most recent work

Find a gap in your own Protein Kinase Regulation and GTPase Signaling sub-topic

This page shows what the Protein Kinase Regulation and GTPase Signaling literature already flags as unresolved. To narrow it to your specific question, run the guided finder — it searches the gap library on demand and checks candidates against 250M+ OpenAlex works.

Open the Research Gap Finder →

Related topics in Biochemistry, Genetics and Molecular Biology

Gut microbiota and health
289 open questions
Single-cell and spatial transcriptomics
185 open questions
dental development and anomalies
121 open questions
Mitochondrial Function and Pathology
110 open questions
Genetic Associations and Epidemiology
106 open questions
Human-Animal Interaction Studies
105 open questions
Genomics and Chromatin Dynamics
97 open questions
Inflammatory Bowel Disease
91 open questions
32 open questions have been extracted from the limitations and future-work passages of 110 Protein Kinase Regulation and GTPase Signaling papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

Tools for your next paper

Gaps & Literature SearchFind open questions in any field — 120,000+ open gaps mined from our own library.Pre-CheckIs your paper ready? A Tier 1–5 acceptance probability in seconds.Journal FinderA ranked shortlist of target journals from a 17,500-venue index.Duplicate Publication CheckerCheck prior-publication & salami-slicing risk across 8 sources.Citation GeneratorFreeA DOI or title → APA, MLA, Vancouver, Chicago, BibTeX, RIS. No signup.Graphical Abstract MakerFreeTurn your findings into a colorblind-safe graphical abstract.

Compare the category — Honest roundups of the AI research tools, ours listed alongside the alternatives.

Command palette

Jump anywhere, run any action.