Date of Award
Spring 2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Molecular Biophysics and Biochemistry
First Advisor
Koleske, Anthony
Abstract
Abl family kinases serve as hubs for signaling cues and cytoskeletal rearrangement to regulate cell morphogenesis and migration. Loss of Abl2 in mice leads to a significant decrease in neuronal dendrite branch complexity accompanied by learning and memory behavioral deficits. Previous studies reveal that Abl2 interacts with microtubules to promote plus-end elongation both in vitro and in cells. However, mechanisms underlying Abl2 regulation of MT dynamics and organization remain understudied. Here, I report that Abl2 interacts with both the MT lattice and tubulin dimers to regulate dynamics. For the first time, I show that Abl2 can undergo phase separation and form coacervates with tubulin, both mediated by its cytoskeleton-binding C-terminal half. I demonstrate that Abl2 promotes MT nucleation, which is facilitated by co-condensation of Abl2 and tubulin dimers. A naturally occurring splice-isoform is tubulin-binding deficient, which underlies its inability to promote MT nucleation. Additionally, my findings reveal that knockout of Abl2 in COS-7 cells inhibits recovery of the MT network after nocodazole treatment. Only Abl2, but not the tubulin-binding deficient Abl2 isoform, can promote MT reassembly. I also discovered that Abl2 mediates repair of damaged MT lattices in vitro and increases MT rescue frequency and lifetime. Collectively, I have shown that Abl2 has two novel regulatory functions that involve the recruitment and addition of tubulin dimers to MTs in different functional scenarios in the cell.
Recommended Citation
Duan, Daisy, "Regulation of Microtubule Nucleation and Repair by an Abl Family Kinase" (2024). Yale Graduate School of Arts and Sciences Dissertations. 1506.
https://elischolar.library.yale.edu/gsas_dissertations/1506
