A cryptic tubulin-binding domain links MEKK1 to curved tubulin protomers

Area of Science:

• Cell Biology
• Molecular Biology
• Cancer Research

Background:

• MEKK1 is a key kinase activator for cellular stress responses.
• MEKK1 activation can initiate signaling pathways like MAP kinases and NF-κB, and influence cell migration.
• Microtubule-targeting chemotherapies activate MEKK1.

Purpose of the Study:

• To investigate the function of a previously unidentified domain in the MEKK1 protein.
• To explore the interaction between MEKK1 and tubulin and its implications in cellular processes.
• To determine the relevance of MEKK1-tubulin association in cancer and response to therapies.

Main Methods:

• Bioinformatic analysis to identify the TOG domain in MEKK1.
• Biochemical assays to study the binding of the MEKK1 TOG domain to tubulin heterodimers.
• Cellular experiments to assess the impact of tubulin binding mutations on microtubule density and cell polarization.
• Analysis of patient-derived tumor sequences for MEKK1 mutations.

Main Results:

• MEKK1 possesses a unique, single tumor overexpressed gene (TOG) domain that binds tubulin heterodimers.
• The MEKK1 TOG domain preferentially binds curved tubulin heterodimers found in soluble tubulin and at microtubule polymerization sites.
• Mutations disrupting MEKK1-tubulin binding reduce microtubule density at the leading edge of polarized cells.
• Recurrent MEKK1 mutations at the tubulin-binding interface are observed in patient tumors, suggesting selective pressure.

Conclusions:

• MEKK1 directly interacts with tubulin through its novel TOG domain.
• This interaction influences microtubule dynamics at the cellular periphery, potentially affecting cell migration.
• The prevalence of MEKK1 mutations in tumors highlights the significance of MEKK1-microtubule association in cancer.
• Findings suggest a role for MEKK1-tubulin binding in cancer cell migration and response to microtubule-based therapies.