Regulation of microtubule dynamics, mechanics and function through the growing tip

Gudimchuk, Nikita; McIntosh, J. Richard

doi:10.1038/s41580-021-00399-x

Cited by 168 publications

(166 citation statements)

References 222 publications

Supporting

Mentioning

125

Contrasting

Unclassified

Order By: Relevance

“…Periods of growth and shrinking alternate in a cycle known as dynamic instability [5]. In cells, an ample cohort of microtubule-associated proteins like the end-binding proteins EB1, EB2, and EB3 regulate this process [6][7][8]. This dynamic turnover of MT polymer is essential for virtually all MT-dependent biological processes.…”

Section: Microtubules and Tubulinmentioning

confidence: 99%

Microtubule Targeting Agents in Disease: Classic Drugs, Novel Roles

Wordeman

Vicente

2021

Cancers

View full text Add to dashboard Cite

Microtubule-targeting agents (MTAs) represent one of the most successful first-line therapies prescribed for cancer treatment. They interfere with microtubule (MT) dynamics by either stabilizing or destabilizing MTs, and in culture, they are believed to kill cells via apoptosis after eliciting mitotic arrest, among other mechanisms. This classical view of MTA therapies persisted for many years. However, the limited success of drugs specifically targeting mitotic proteins, and the slow growing rate of most human tumors forces a reevaluation of the mechanism of action of MTAs. Studies from the last decade suggest that the killing efficiency of MTAs arises from a combination of interphase and mitotic effects. Moreover, MTs have also been implicated in other therapeutically relevant activities, such as decreasing angiogenesis, blocking cell migration, reducing metastasis, and activating innate immunity to promote proinflammatory responses. Two key problems associated with MTA therapy are acquired drug resistance and systemic toxicity. Accordingly, novel and effective MTAs are being designed with an eye toward reducing toxicity without compromising efficacy or promoting resistance. Here, we will review the mechanism of action of MTAs, the signaling pathways they affect, their impact on cancer and other illnesses, and the promising new therapeutic applications of these classic drugs.

show abstract

Section: Microtubules and Tubulinmentioning

confidence: 99%

Microtubule Targeting Agents in Disease: Classic Drugs, Novel Roles

Wordeman

Vicente

2021

Cancers

View full text Add to dashboard Cite

show abstract

“…Schematic of AFM imaging illustrates the distinct structural dynamics and intermediates during microtubule depolymerization with different enzymes and its impact on microtubule arrays. In the context of an individual microtubule: (1) the depolymerization of protofilaments is asynchronous with MCAK and synchronous with Kip3p, and (2) MCAK propagates lattice defects whereas Kip3p does not. In the context of microtubule arrays: (1) Crosslinking by PRC1 protects microtubules against depolymerization by MCAK and does not significantly influence the depolymerization by Kip3p, and (2) MCAK depolymerizes doublet microtubules and results in the destabilization of axonemal arrays.…”

Section: Discussionmentioning

confidence: 99%

“…Microtubules themselves are complex cylindrical macromolecular assembly of, most commonly, 13-15 protofilaments that are composed of repeating α,β-tubulin heterodimers. The intrinsic dynamic instability of microtubules and its regulation by a host of different Microtubule Associated Proteins (MAPs) are critical for the assembly and disassembly of microtubule arrays (1). How nanometer-scale dynamics of protofilaments (~4 nm) and microtubules (~25 nm) result in the organization and remodeling of micron-sized multi-microtubule arrays remains poorly understood.…”

Section: Main Textmentioning

confidence: 99%

“…We used two main criteria to set the imaging conditions for investigating microtubule dynamics within PRC1-crosslinked bundles (3-4 mins/frame with 256 x 256 pixels): (1) the spatial and temporal resolution is suitable for imaging the entire array as well as individual microtubules within the bundle, and (2) no sample damage is visible in the time frame of the experiment (15-30 mins). Experiments were performed with both GMPCPP- and GMPCPP + taxol-stabilized microtubules.…”

Section: Main Textmentioning

confidence: 99%

See 1 more Smart Citation

Atomic Force Microscopy Reveals Distinct Protofilament-scale Structural Dynamics in Depolymerizing Microtubule Arrays

Wijeratne

Marchan

Tresback

et al. 2020

Preprint

View full text Add to dashboard Cite

SUMMARYThe intrinsic dynamic instability of microtubules and their control by associated enzymes, such as depolymerases, are essential for the organization of complex multi-microtubule arrays like spindle and axoneme. However, existing optical or electron-microscopy methods lack the spatial-temporal resolution to observe the dynamics of individual microtubules within arrays. We use Atomic Force Microscopy (AFM) to image depolymerizing arrays at single microtubule and protofilament resolution. We discover previously unseen modes of microtubule destabilization by conserved depolymerases. The kinesin-13 MCAK mediates asynchronous protofilament depolymerization and lattice-defect propagation, whereas the kinesin-8 Kip3p promotes synchronous protofilament depolymerization. Unexpectedly, MCAK can depolymerize axonemal doublets but Kip3p cannot. We propose that distinct protofilament-level activities underlie the functional dichotomy of depolymerases, resulting in either large-scale destabilization or length regulation of microtubule arrays. Our work establishes AFM as a powerful strategy to visualize microtubule dynamics and reveals how nanometer-scale substrate specificity leads to differential remodeling of micron-sized cytoskeletal structures.

show abstract

“…Several microtubule-associated proteins (MAPs) contribute to the elongation of the tubulin filaments [9]. Essential among them is the tubulin adaptor protein Collapsin Response Mediator Protein 2 (CRMP2), a ubiquitously expressed phosphoprotein best known for its affinity for tubulin heterodimers.…”

Section: Introductionmentioning

confidence: 99%

CRMP2 as a Candidate Target to Interfere with Lung Cancer Cell Migration

et al. 2021

View full text Add to dashboard Cite

Collapsin response mediator protein 2 (CRMP2) is an adaptor protein that adds tubulin dimers to the growing tip of a microtubule. First described in neurons, it is now considered a ubiquitous protein that intervenes in processes such as cytoskeletal remodeling, synaptic connection and trafficking of voltage channels. Mounting evidence supports that CRMP2 plays an essential role in neuropathology and, more recently, in cancer. We have previously described a positive correlation between nuclear phosphorylation of CRMP2 and poor prognosis in lung adenocarcinoma patients. In this work, we studied whether this cytoskeleton molding protein is involved in cancer cell migration. To this aim, we evaluated CRMP2 phosphorylation and localization in the extending lamella of lung adenocarcinoma migrating cells using in vitro assays and in vivo confocal microscopy. We demonstrated that constitutive phosphorylation of CRMP2 impaired lamella formation, cell adhesion and oriented migration. In search of a mechanistic explanation of this phenomenon, we discovered that CRMP2 Ser522 phospho-mimetic mutants display unstable tubulin polymers, unable to bind EB1 plus-Tip protein and the cortical actin adaptor IQGAP1. In addition, integrin recycling is defective and invasive structures are less evident in these mutants. Significantly, mouse xenograft tumors of NSCLC expressing CRMP2 phosphorylation mimetic mutants grew significantly less than wild-type tumors. Given the recent development of small molecule inhibitors of CRMP2 phosphorylation to treat neurodegenerative diseases, our results open the door for their use in cancer treatment.

show abstract

Regulation of microtubule dynamics, mechanics and function through the growing tip

Cited by 168 publications

References 222 publications

Microtubule Targeting Agents in Disease: Classic Drugs, Novel Roles

Microtubule Targeting Agents in Disease: Classic Drugs, Novel Roles

Atomic Force Microscopy Reveals Distinct Protofilament-scale Structural Dynamics in Depolymerizing Microtubule Arrays

CRMP2 as a Candidate Target to Interfere with Lung Cancer Cell Migration

Contact Info

Product

Resources

About