Understanding the molecular mechanisms that regulate cell shape and motility is essential for treatment of neurological diseases. Several diseases such as schizophrenia and epilepsy are associated with defects in synaptic function and neuronal morphology. Abl family nonreceptor tyrosine kinases (Abl and Arg) are necessary for proper cellular morphogenesis in the developing nervous system and for synaptic function and neuronal morphology in the adult mouse brain. These processes depend on dramatic reorganizations of the actin-based cytoskeleton. Arg harbors two distinct F-actin-binding domains. It uses these domains to bundle actin filaments in vitro and to induce the formation of actin-rich structures at the lamellipodia of fibroblasts. These kinases may influence neuronal and/or synaptic morphology and motility by controlling the actin cytoskeleton. The experiments proposed here will investigate how Arg's actin-binding and bundling abilities regulate cell motility and growth factor-induced rearrangements of the actin cytoskeleton.
The first aim i s to establish a system for measuring Arg's localization and movement in cells using abl-/-arg-/-fibroblasts reconstituted with an Arg-yellow fluorescent fusion protein.
The second aim i s to measure Arg-dependent changes in cell motility and to determine whether Arg's regulation of motility is dependent on kinase activity or actin-binding and bundling activity.
The third aim i s to examine whether Arg's ability to bind and bundle actin plays a role in the cytoskeletal rearrangements that result from growth factor stimulation. These studies should lead to a better understanding of how actin cytoskeletal changes regulate neuronal morphology, motility, and function in normal neurons and how this regulation breaks down in neurological diseases.
| Peacock, Justin G; Miller, Ann L; Bradley, William D et al. (2007) The Abl-related gene tyrosine kinase acts through p190RhoGAP to inhibit actomyosin contractility and regulate focal adhesion dynamics upon adhesion to fibronectin. Mol Biol Cell 18:3860-72 |
| Miller, Ann L; Wang, Yinxiang; Mooseker, Mark S et al. (2004) The Abl-related gene (Arg) requires its F-actin-microtubule cross-linking activity to regulate lamellipodial dynamics during fibroblast adhesion. J Cell Biol 165:407-19 |
| Hernandez, Samuel E; Krishnaswami, Maithreyi; Miller, Ann L et al. (2004) How do Abl family kinases regulate cell shape and movement? Trends Cell Biol 14:36-44 |
