Taxane-Induced Conformational Changes in the Microtubule Lattice Activate GEF-H1-Dependent RhoA Signaling
Posted on: 31 December 2025
Preprint posted on 23 December 2025
More than just a stabilizer: Taxanes (cancer drugs) trigger the GEF-H1 – RhoA axis.
Selected by Vibha SINGH
Categories: cancer biology, cell biology
Context and rationale
Microtubule-Targeting Agents (MTAs) are chemotherapeutics, conventionally thought to stop tumor cell division by mitotic arrest. However, limited clinical success of drugs targeting mitotic arrest suggests that non-mitotic, interphase effects of MTAs are rather relevant for their therapeutic efficacy. Although microtubule-destabilizing agents activate the RhoA signaling pathway by releasing RhoA-GEF, GEF-H1 (or Arhgef2), the mechanism of how MTAs (like taxanes) affect this signaling remains ambiguous.
The authors of this preprint hypothesized that taxanes could potentially activate the GEF-H1 – RhoA signalling axis based on recent emerging evidence indicating that microtubule (MT) stabilization alters lattice conformation and post-translational modifications, and displaces microtubule associated GEF-H1 in cytosol.
Key findings of the study
- Conformational code (Taxanes trigger GEF-H1 – RhoA signaling)
The shape of the microtubule lattice, compact versus expanded, functions as a biological conformational code. This explanation contradicts the earlier description in literature that emphasized the effect mainly on chemical tags (tubulin code). Data in this preprint demonstrate that GEF-H1 is a “reader” of the microtubule conformational code; it favors a compacted microtubule lattice. Paclitaxel and docetaxel, MT stabilization agents, induce RhoA activation, which is weaker and significantly slower than MT de-stabilizing agents (like nocodazole) but act at clinically relevant taxane concentrations. This effect was abolished in cells lacking GEF-H1, indicating stable MTs require GEF-H1 for RhoA activation. Overall, these findings suggest that taxanes do not just “freeze” the cellular skeleton; it actively alters the spacing of molecules (lattice). Association of GEF-H1 with microtubules is highly sensitive to this lattice conformation.
- Taxanes trigger GEF-H1-dependent actin remodeling
Although it is well known that paclitaxel stabilizes MTs, this study demonstrates that it causes physical longitudinal expansion (stretching) of the microtubule lattice. This stretched lattice forces GEF-H1 to detach from MTs, which then triggers RhoA signaling, actomyosin contractility, actin remodeling, and cell rounding. Although, these finding appear similar to those caused by the MT de-stabilizing agent nocodazole, the mechanism by which GEF-H1 is dissociated from MTs is different.
- Paclitaxel modifies microtubule lattice conformation and displaces GEF-H1
Paclitaxel quickly displaces GEF-H1 from MTs prior to MT acetylation. Further, the authors report that another MT stabilizing agent, discodermolide, despite stabilizing MT, does not displace GEF-H1, confirming that this is a paclitaxel-specific regulation. In vitro reconstitution assays further convincingly validate that paclitaxel-induced expanded MT lattice directly displaces GEF-H1, whereas discodermolide-bound compact lattices hold bound GEF-H1.
What I like most about the preprint
I really enjoyed reading about the key in-vitro constitution and lattice expansion experiments, which establish the causality of paclitaxel-induced GEF-H1 – RhoA-axis activation (Figure 1). This is a rather compelling finding as it disconnects “microtubule stabilization” from “microtubule lattice conformation”, which is a relevant trigger code.
Figure 1. (A) (Reproduced from Preprint Figure S4). Illustration of microtubule lattice parameters: dimer rise, which reflects lattice expansion and compaction. Schematic representation of GEF-H1 C1 binding to the microtubule lattice, based on (Choi et al., 2025). (B) A cartoon summarizing taxane regulating GEF-H1 – RhoA signaling.
Significance of this study
The findings reported in this study are significant as they help explain the clinical efficacy of taxanes and why they are different from mitosis arrest targeted drugs. It emphasizes microtubules are not just cellular cytoskeleton but are active conformation-sensitive signaling hubs, proposing new mechanical pathways and guidelines for selective anticancer therapies.
Open Questions
Q1: Do paclitaxel-treated cells affect cell migration or invasion in GEF-H1-dependent manner?
Q2: Do you anticipate GEF-H1 or RhoA activity could serve as a biomarker for taxane response in tumors?
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