New perspectives on the roles of Abl tyrosine kinase in axon patterning

Kannan, R.; Giniger, Edward

doi:10.1080/19336934.2017.1327106

Cited by 14 publications

(13 citation statements)

References 69 publications

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“…Abelson tyrosine kinase (Abl) is an essential protein that is a key regulator of cytoskeletal dynamics. Abl is known to aid in the regulation of actin dynamics underlying a myriad of cell processes, ranging from vesicle trafficking and Golgi architecture to cell motility and development [ 1 – 4 ]. Yet, understanding how Abl functions in these cellular processes remains challenging.…”

Section: Introductionmentioning

confidence: 99%

Long disordered regions of the C-terminal domain of Abelson tyrosine kinase have specific and additive functions in regulation and axon localization

Cheong

VanBerkum

2017

PLoS ONE

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Abelson tyrosine kinase (Abl) is a key regulator of actin-related morphogenetic processes including axon guidance, where it functions downstream of several guidance receptors. While the long C-terminal domain (CTD) of Abl is required for function, its role is poorly understood. Here, a battery of mutants of Drosophila Abl was created that systematically deleted large segments of the CTD from Abl or added them back to the N-terminus alone. The functionality of these Abl transgenes was assessed through rescue of axon guidance defects and adult lethality in Abl loss-of-function, as well as through gain-of-function effects in sensitized slit or frazzled backgrounds that perturb midline guidance in the Drosophila embryonic nerve cord. Two regions of the CTD play important and distinct roles, but additive effects for other regions were also detected. The first quarter of the CTD, including a conserved PxxP motif and its surrounding sequence, regulates Abl function while the third quarter localizes Abl to axons. These regions feature long stretches of intrinsically disordered sequence typically found in hub proteins and are associated with diverse protein-protein interactions. Thus, the CTD of Abl appears to use these disordered regions to establish a variety of different signaling complexes required during formation of axon tracts.

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Section: Introductionmentioning

confidence: 99%

Long disordered regions of the C-terminal domain of Abelson tyrosine kinase have specific and additive functions in regulation and axon localization

Cheong

VanBerkum

2017

PLoS ONE

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“…Indeed, TACC3 and XMAP215 can rescue each other’s downregulation phenotypes in axon elongation, and it has been suggested that TACC3 strengthens the XMAP215-TACC3 complex binding to MTs in order to drive polymerization activity ( Nwagbara et al, 2014 ; Erdogan et al, 2017 ). TACC3 is a phosphorylation target of the kinase Abl, whose activity is known to be regulated by axon guidance signaling ( Kannan and Giniger, 2017 ). A TACC3 phospho-null mutant failed to localize at MT plus-ends in GCs, leading to an increase of MT invasion into the filopodia and impaired axon pathfinding.…”

Section: Microtubule-associated Proteins In Axon Guidancementioning

confidence: 99%

With the Permission of Microtubules: An Updated Overview on Microtubule Function During Axon Pathfinding

Sánchez-Huertas

Herrera

2021

Front. Mol. Neurosci.

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During the establishment of neural circuitry axons often need to cover long distances to reach remote targets. The stereotyped navigation of these axons defines the connectivity between brain regions and cellular subtypes. This chemotrophic guidance process mostly relies on the spatio-temporal expression patterns of extracellular proteins and the selective expression of their receptors in projection neurons. Axon guidance is stimulated by guidance proteins and implemented by neuronal traction forces at the growth cones, which engage local cytoskeleton regulators and cell adhesion proteins. Different layers of guidance signaling regulation, such as the cleavage and processing of receptors, the expression of co-receptors and a wide variety of intracellular cascades downstream of receptors activation, have been progressively unveiled. Also, in the last decades, the regulation of microtubule (MT) assembly, stability and interactions with the submembranous actin network in the growth cone have emerged as crucial effector mechanisms in axon pathfinding. In this review, we will delve into the intracellular signaling cascades downstream of guidance receptors that converge on the MT cytoskeleton of the growing axon. In particular, we will focus on the microtubule-associated proteins (MAPs) network responsible of MT dynamics in the axon and growth cone. Complementarily, we will discuss new evidences that connect defects in MT scaffold proteins, MAPs or MT-based motors and axon misrouting during brain development.

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“…Others built on these efforts. Like its mammalian homologs, Abl plays important roles in embryonic and postembryonic neural development, acting downstream of diverse axon guidance receptors, including DCC/Frazzled, Robo, Plexin, Eph, and Notch (reviewed in [ 6 ]. Genetic and cell biological analyses also revealed Abl’s downstream effectors, the most prominent of which is Enabled (Ena), which binds the growing end of actin filaments and promotes their elongation.…”

Section: Introductionmentioning

confidence: 99%

Abelson kinase’s intrinsically disordered region plays essential roles in protein function and protein stability

2021

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Background The non-receptor tyrosine kinase Abelson (Abl) is a key player in oncogenesis, with kinase inhibitors serving as paradigms of targeted therapy. Abl also is a critical regulator of normal development, playing conserved roles in regulating cell behavior, brain development and morphogenesis. Drosophila offers a superb model for studying Abl’s normal function, because, unlike mammals, there is only a single fly Abl family member. In exploring the mechanism of action of multi-domain scaffolding proteins like Abl, one route is to define the roles of their individual domains. Research into Abl’s diverse roles in embryonic morphogenesis revealed many surprises. For instance, kinase activity, while important, is not crucial for all Abl activities, and the C-terminal F-actin binding domain plays a very modest role. This turned our attention to one of Abl’s least understood features—the long intrinsically-disordered region (IDR) linking Abl’s kinase and F-actin binding domains. The past decade revealed unexpected, important roles for IDRs in diverse cell functions, as sites of posttranslational modifications, mediating multivalent interactions and enabling assembly of biomolecular condensates via phase separation. Previous work deleting conserved regions in Abl’s IDR revealed an important role for a PXXP motif, but did not identify any other essential regions. Methods Here we extend this analysis by deleting the entire IDR, and asking whether Abl∆IDR rescues the diverse roles of Abl in viability and embryonic morphogenesis in Drosophila. Results This revealed that the IDR is essential for embryonic and adult viability, and for cell shape changes and cytoskeletal regulation during embryonic morphogenesis, and, most surprisingly, revealed a role in modulating protein stability. Conclusion Our data provide new insights into the role of the IDR in an important signaling protein, the non-receptor kinase Abl, suggesting that it is essential for all aspects of protein function during embryogenesis, and revealing a role in protein stability. These data will stimulate new explorations of the mechanisms by which the IDR regulates Abl stability and function, both in Drosophila and also in mammals. They also will stimulate further interest in the broader roles IDRs play in diverse signaling proteins.

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New perspectives on the roles of Abl tyrosine kinase in axon patterning

Cited by 14 publications

References 69 publications

Long disordered regions of the C-terminal domain of Abelson tyrosine kinase have specific and additive functions in regulation and axon localization

Long disordered regions of the C-terminal domain of Abelson tyrosine kinase have specific and additive functions in regulation and axon localization

With the Permission of Microtubules: An Updated Overview on Microtubule Function During Axon Pathfinding

Abelson kinase’s intrinsically disordered region plays essential roles in protein function and protein stability

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