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Target: TUBB3


Research on TUBB3

1. Target Summary:

TUBB3, or Tubulin Beta-3, is a member of the tubulin family of proteins that are essential components of the cytoskeleton in eukaryotic cells. It is predominantly expressed in neurons and plays a critical role in microtubule dynamics, which are vital for neuronal development, axon guidance, and synaptic function. Mutations in TUBB3 have been implicated in various neurological disorders, including congenital fibrosis of the extraocular muscles and other neurodevelopmental disorders. Additionally, TUBB3 is associated with cancer biology, particularly in glioblastoma and breast cancer, where its expression correlates with tumor aggressiveness and drug resistance.

2. Mechanism:

TUBB3 functions primarily as a structural protein that forms microtubules, which are dynamic filaments that provide structural support and facilitate intracellular transport. The mechanism of action of TUBB3 involves several key processes:
  • Microtubule Dynamics: TUBB3 contributes to the assembly and disassembly of microtubules, which is crucial for maintaining neuronal shape and facilitating axonal transport. It interacts with various microtubule-associated proteins (MAPs) that regulate microtubule stability and dynamics (Romaniello et al., 2015, PMID: 25008804).
  • Axon Guidance: TUBB3 is involved in axon guidance through its interaction with netrin receptors. Mutations in TUBB3 can disrupt this signaling pathway, leading to defects in neuronal migration and axon pathfinding (Shao et al., 2019, PMID: 31226147).
  • GABA-A Receptor Trafficking: TUBB3 has been shown to interact with GABA-A receptor-associated proteins, influencing the trafficking and surface expression of GABA-A receptors, which are critical for inhibitory neurotransmission in the brain (Xu et al., 2017, PMID: 28378416).

3. Approved Drugs:

Currently, there are no specific drugs approved that target TUBB3 directly. However, TUBB3 expression is a biomarker for sensitivity to certain chemotherapeutic agents, such as taxanes (e.g., paclitaxel) and platinum-based therapies. Drugs that target microtubules, including taxanes, may indirectly affect TUBB3-related pathways.

4. Hypotheses:

Several hypotheses regarding TUBB3's role in disease have been proposed:
  • Neurological Disorders: It is hypothesized that mutations in TUBB3 lead to abnormal microtubule dynamics, resulting in impaired neuronal migration and differentiation, which contribute to various neurodevelopmental disorders (Tischfield et al., 2011, PMID: 21292473).
  • Cancer Progression: TUBB3 is thought to play a role in the aggressiveness of tumors, particularly in glioblastoma and breast cancer, by promoting invasive capabilities and resistance to chemotherapeutic agents (Katsetos et al., 2009, PMID: 19650075).

5. Validation:

The role of TUBB3 in neurological disorders and cancer has been validated through various studies:
  • Genetic Studies: Numerous studies have identified mutations in TUBB3 associated with specific neurological phenotypes, supporting its role in neuronal development (Romaniello et al., 2015, PMID: 25008804).
  • Clinical Correlations: Elevated TUBB3 expression has been correlated with poor prognosis in cancer patients, particularly in those with glioblastoma and breast cancer, validating its role as a potential therapeutic target (Miyata et al., 2018, PMID: 29491095).

6. Clinical Trials:

While there are no specific clinical trials targeting TUBB3 directly, ongoing research is exploring the implications of TUBB3 expression in treatment responses to existing chemotherapeutics in various cancers. Trials focusing on taxane-based therapies often consider TUBB3 expression as a predictive biomarker.

7. Involved Pathways:

TUBB3 is involved in several key cellular pathways, including:
  • Microtubule Dynamics Pathway: Regulates the assembly and disassembly of microtubules, crucial for cell shape and intracellular transport.
  • Netrin Signaling Pathway: Involved in axon guidance and neuronal migration.
  • GABAergic Signaling Pathway: Influences inhibitory neurotransmission through GABA-A receptor trafficking.

8. Associated Genes:

TUBB3 interacts with several other genes and proteins, including:
  • MAPs (Microtubule-Associated Proteins): Regulate microtubule stability.
  • Netrin Receptors: Involved in axon guidance.
  • GABA-A Receptor-Associated Proteins: Affect GABA receptor trafficking.

9. Target Expression:

TUBB3 is predominantly expressed in neuronal tissues, with significant upregulation observed in various cancers, including glioblastoma and breast cancer. Its expression levels can serve as a prognostic marker for treatment outcomes.

10. Additional Context:

Understanding TUBB3's role in both neurological disorders and cancer provides insights into potential therapeutic strategies. Targeting TUBB3-related pathways may enhance treatment efficacy and improve patient outcomes in both fields.

11. References:

  • Romaniello R, Arrigoni F, Bassi MT. Mutations in alpha- and beta-tubulin encoding genes: implications in brain malformations. Brain & development. 2015 Mar; PMID: 25008804.
  • Shao Q, Yang T, Huang H. Disease-associated mutations in human TUBB3 disturb netrin repulsive signaling. PloS one. 2019; PMID: 31226147.
  • Xu X, Shangguan Y, Lu S. Tubulin beta-III modulates seizure activity in epilepsy. The Journal of pathology. 2017 Jul; PMID: 28378416.
  • Katsetos CD, Draberova E, Legido A. Tubulin targets in the pathobiology and therapy of glioblastoma multiforme. I. Class III beta-tubulin. Journal of cellular physiology. 2009 Dec; PMID: 19650075.
  • Miyata Y, Matsuo T, Nakamura Y. Expression of Class III Beta-tubulin Predicts Prognosis in Patients with Cisplatin-resistant Bladder Cancer Receiving Paclitaxel-based Second-line Chemotherapy. Anticancer research. 2018 Mar; PMID: 29491095.