Open research questions in Protein Kinase Regulation and GTPase Signaling
99 gap statements mined from Protein Kinase Regulation and GTPase Signaling papers in our 4.5M-paper local library, which holds 316 papers on the topic — drawn mostly from each paper's own stated research gap, future-work, challenge and limitation notes, and its abstract. The ones listed below are a selection still marked open; each names the study that raised it, with a DOI link where the paper has one.
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What the literature leaves open
The study of cell-cell contact formation is complex due to the involvement of multiple cellular processes. The depletion of RhoGDI1 can have pleiotropic effects on cellular processes, making it challenging to interpret the results. The recruitment of RhoGDI1 to cell-cell contacts by JAM-A is a complex process that requires further investigation.
The prognosis for OSCC patients remains poor, particularly in advanced stages. Current treatments often fail to improve the prognosis for patients with advanced OSCC. There is a need for new and effective therapies for OSCC.
further investigation in both preclinical and clinical contexts, - development of Parishin A as a novel therapeutic agent for OSCC, - research to improve patient prognosis and reduce the burden of this aggressive cancer
Cholecystokinin (CCK), a neuropeptide abundant in the ventral tegmental area (VTA), modulates addiction-related behaviors through its receptors (CCK1R/CCK2R), yet its role in METH-induced conditioned place preference (CPP) remains unclear.
Finally, we address several underexplored clinical avenues regarding SOS1 inhibition for the treatment of specific cancer subtypes.
SOS1: tracking the evolving path from promising to actionable therapeutic target in RAS-dependent cancers · 2026 · DOIHowever, the mechanistic basis underlying the effective combined targeting of KRAS and MYC remains poorly defined, largely due to the complexity of their functional interplay.
Rho GTPase-activating protein 21 (ARHGAP21) plays a role in the occurrence and development of certain cancers, but its function in hepatocellular carcinoma (HCC) remains unclear.
ARHGAP21 enhances metastasis in hepatocellular carcinoma by inhibiting ubiquitination of filamin A · 2026 · DOIPleckstrin homology (PH) domains are typically assumed to be phosphoinositide-binding modules, although most lack strong lipid specificity and their broader ligand repertoire remains poorly defined.
Despite notable successes of small-molecule inhibitors in the treatment of KRASG12C cancer, many of these small-molecule inhibitors preferentially bind to inactive (GDP-bound) mutant KRAS, whose availability is limited by the slow rate of intrinsic GTP hydrolysis.
How KRAS Mutations Impair Intrinsic GTP Hydrolysis: Experimental and Computational Investigations · 2025 · DOIHowever, the structural basis for the negative regulation of ABA signaling by ROP GTPases remains elusive.
Despite its importance, the cellular mechanisms that modulate PAK1 function remain poorly understood.
SIGNIFICANCE: RAS inhibitors have shown early evidence of efficacy in multiple cancer types, but clinical benefit is limited by acquired resistance.
The current research mainly focuses on studying the role of PAK and PAK inhibitors in the regulation of cancer progression, but relatively few reports are available that explore their potential role in cardiovascular diseases.
Regulation of Vascular Injury and Repair by P21-Activated Kinase 1 and P21-Activated Kinase 2: Therapeutic Potential and Challenges · 2024 · DOIHowever, the specific cellular mechanisms that are driven by Gsα and contribute to the development of atherosclerosis remain unclear.
The molecular mechanisms underlying seizure generation remain elusive, yet they are crucial for developing effective treatments for epilepsy.
Prophylactic treatment with the c-Abl inhibitor, neurotinib, diminishes neuronal damage and the convulsive state in pilocarpine-induced mice · 2024 · DOIThe molecular mechanism by which ligand recognition initiates γδ TCR signaling, a process known as TCR triggering, remains elusive.
Ligand-induced segregation from large cell-surface phosphatases is a critical step in γδ TCR triggering · 2024 · DOIFirst-generation KRAS G12C inhibitors, such as sotorasib and adagrasib, are limited by the depth and duration of clinical responses.
D3S-001, a KRAS G12C Inhibitor with Rapid Target Engagement Kinetics, Overcomes Nucleotide Cycling, and Demonstrates Robust Preclinical and Clinical Activities · 2024 · DOIFollow-up studies on the top hits through counter screening for these residues against other RAS isoforms. Exploration of the therapeutic potential of the identified pockets. Application of the disulfide tethering approach to other proteins, particularly GTPases.
KRAS is a challenging target due to its high nucleotide affinity and perceived absence of binding sites. There is a need for effective strategies to discover pockets on KRAS. Prior approaches have focused on targeting known interfaces, leaving cryptic pockets unexplored.
Development of new RAS-targeted therapies. Investigation of KRAS-specific inhibitors in clinical trials. Further research on RAS biology and function.
The heart of the matter: a personal view of Fred Wittinghofer’s contributions to RAS biology and drug design · 2026 · DOIRAS proteins are challenging to target with drugs. Limited understanding of RAS function and regulation.
The heart of the matter: a personal view of Fred Wittinghofer’s contributions to RAS biology and drug design · 2026 · DOIThe development of effective RAS inhibitors has been limited by the difficulty of targeting RAS proteins. The identification of a druggable pocket on SOS1 has provided a new opportunity for the development of RAS inhibitors.
Disrupting the KRAS–SOS1 protein–protein interaction: mechanistic rationale for pan-KRAS pathway suppression and combination therapy · 2026 · DOIA 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 · DOIThe paper identifies a gap in our understanding of the complex interactions between Rho GTPases and other signalling pathways. The paper highlights the need for further research on the physiological and pathological impacts of Rho GTPase-regulated cell migration.
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.
Most-cited papers in Protein Kinase Regulation and GTPase Signaling
- Rho GTPases in cell biology · Nature · 2002 · 4,023 citations
- The molecular heterogeneity of protein kinase C and its implications for cellular regulation · Nature · 1988 · 3,231 citations
- The GTPase superfamily: conserved structure and molecular mechanism · Nature · 1991 · 2,722 citations
- Regulation of Myosin Phosphatase by Rho and Rho-Associated Kinase (Rho-Kinase) · Science · 1996 · 2,439 citations
- The Rag GTPases Bind Raptor and Mediate Amino Acid Signaling to mTORC1 · Science · 2008 · 2,433 citations
- Pan-KRAS inhibitor disables oncogenic signalling and tumour growth · Nature · 2023 · 518 citations
- Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy · Nature · 2024 · 317 citations
- Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants · Cancer Discovery · 2022 · 308 citations
- Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers · Cancer Discovery · 2024 · 284 citations
- Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer · Cancer Discovery · 2024 · 239 citations
Most recent work
- Emerging landscape of KRAS inhibitors in cancer treatment · Cancer Cell · 2026
- Allosteric Binding-Mediated Suppression on Activity of G12D KRAS Recognized via Markov State Model and Communication Pathway · The Journal of Physical Chemistry B · 2026
- Citrate clearance is a major function of aconitase 2 in the canonical TCA cycle · Cell · 2026
- Discovery of BBO-11818, a Potent and Selective Noncovalent Inhibitor of (ON) and (OFF) KRAS with Activity against Multiple Oncogenic Mutants · Cancer Discovery · 2026
- Preclinical Characterization and Clinical Activity of RNK08954, a Highly Selective and Orally Bioavailable KRAS G12D Inhibitor · Cancer Discovery · 2026
- Long-range mutual activation establishes Rho and Rac polarity during cell migration · Nature Cell Biology · 2026
- Engineered protein circuits for cancer therapy · bioRxiv · 2026
- Rational discovery of therapeutic PAK1 allosteric activators · Cell · 2026
- Discovery and Optimization of a Potent, Efficacious, and Brain-Penetrant Inhibitor of KRAS G12C · Journal of Medicinal Chemistry · 2026
- Overcoming Adaptive Resistance to KRASG12D Blockade in Pancreatic Cancer through Vertical Pathway Inhibition · Clinical Cancer Research · 2026
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