Tubulin heterogeneity regulates functions and dynamics of microtubules and plays a role in the development of drug resistance in cancer

Abstract

Microtubules, composed of αβ-tubulin heterodimers, exhibit diverse structural and functional properties in different cell types. The diversity in the microtubule structure originates from tubulin heterogeneities, namely tubulin isotypes and their post-translational modifications (PTMs). These heterogeneities confer differential stability to microtubules and provide spatial cues for the functioning of the cell. Furthermore, the altered expressions of tubulin isotypes and PTMs are prominent factors for the development of resistance against some cancer drugs. In this review, we summarize our current knowledge of the tubulin isotypes and PTMs and how, together, they control the cellular functions of the microtubules. We also describe how cancer cells use this tubulin heterogeneity to acquire resistance against clinical agents and discuss existing attempts to counter the developed resistance.

Advances in Understanding TKS4 and TKS5: Molecular Scaffolds Regulating Cellular Processes from Podosome and Invadopodium Formation to Differentiation and Tissue Homeostasis

“…A guanine nucleotide exchange factor promoting Ras and Rac activation downstream of a variety of receptors such as RTKs [70] Tubulin [29] GST pull-down assay and mass spectrometry 3rd SH3 domain Component of microtubules, affects cell division, differentiation, intracellular transport, motility [71] WIP [29] GST pull-down assay and mass spectrometry 3rd and 5th SH3 domains Regulation of actin cytoskeleton assembly and remodeling [72] XB130 [73] Yeast two-hybrid screening, co-immunoprecipitation, GST pull-down assay, immunofluorescence co-localization 5th SH3 domain A scaffold protein influencing cell growth, survival, and migration [73] Zyxin [29] GST pull-down assay and mass spectrometry 3rd and 5th SH3 domains A focal adhesion protein involved in actin cytoskeleton assembly [74] In recent years, more possible interaction partners of TKS4 have been identified (Table 1a). One possible partner is cortactin [9], a well-known substrate of SRC localized to cortical actin structures within cells.…”

Introducing variability in targeting the microtubules: Review of current mechanisms and future directions in colchicine therapy

“…The altered expression of these isotypes and PTMs are associated with the development of resistance toward anti-malignant medications. 2 MTs are also involved in the function of both the innate and adaptive immune systems, making them potential targets for immunomodulation. 13 MTs, through crosstalk with the antigen-receptor signal transduction machinery, are associated with the formation of the immune synapse (IS).…”

Intrinsic and Extrinsic Factors Affecting Microtubule Dynamics in Normal and Cancer Cells

“…The molecular surfaces of tubulins are very similar, considering the level of amino acid similarity, which for α-tubulins reaches approximately 90-95%, and is slightly lower for β-tubulins at 85-95% (with βVI being the most divergent, with approximately 75% similarity to other isotypes). Most amino acid substitutions are accumulated within the C-terminal tubulin tail ( Table 1), suggesting that this part could be responsible for the potential variation of properties of tubulin isotypes and, subsequently, the differences in MT dynamics [29]. However, several β isotypes also have unique substitutions in other regions important for the formation of functional surfaces and pockets.…”

“…Changes in the level of tubulin modifications were linked to tumorigenesis (Table 3) [29,244]. Downregulation of TTL and increased α-tubulin detyrosination were reported during the epithelial-mesenchymal transition (EMT) that occurs during tumor invasion [245] in prostate cancer cells [246], in aggressive subtypes of breast cancer cells [247], and in primary neuroblastomas with poor prognosis [248].…”

“…The human genome encodes seven α- and nine β-tubulin isotypes [ 29 ]. As a consequence, MTs composed of mixed combinations of α- and β-tubulin isotypes show tissue and developmental stage specificity and different properties in different cell types [ 30 , 31 ].…”