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Access Type

WSU Access

Date of Award

January 2019

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Biological Sciences

First Advisor

Mark F. VanBerkum

Abstract

Abelson tyrosine kinase (Abl) is a key player in axon guidance, where it functions to link a multitude of axon guidance receptors to actin cytoskeletal dynamics. The C-terminal domain (CTD) of Abl is instrumental to Abl function, but its role is poorly explored due to a lack of conserved sequence elements. Here, we use a systematic approach to identify regions of the CTD important for Abl function, and define two regions (the first and third quarters, 1Q and 3Q) important for Abl function. We demonstrate that both these regions are likely intrinsically disordered, and function in scaffolding to recruit Abl partners. The 1Q region is essential for Abl function, and interacts with members of the actin-associated Wave regulatory complex (WRC). 1Q’s interaction with the WRC may be mediated through two motifs: a PxxP motif that likely binds the Abelson-interacting (Abi) subunit of the WRC, and a WIRS motif that likely binds the Abi and Sra-1 subunits of the WRC. Interestingly, 1Q is also required for Abl to function with the actin-associated protein Enabled (Ena). Ena is thought to bind directly to Abl, and also to the Abi subunit of the WRC. Thus, the Ena-Abi interaction is likely critical for Abl to coordinate the function of Ena and the WRC in actin dynamics through 1Q. In comparison, the 3Q region helps recruit Abl down the axon of neurons, and physically interacts with actin and a multitude of actin-associated proteins, including the spectrin complex. Abl’s interaction with the spectrin complex does not aid in recruiting Abl to axons. However, the spectrin genes cooperate with Abl in axon guidance, perhaps specifically downstream of the Slit-Roundabout pathway. Overall, it is clear that scaffolding functions of the Abl CTD mediates Abl’s ability to function with multiple actin-associated proteins to allow upstream axon guidance receptors to modulate actin cytoskeletal dynamics.

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