The Tyrosine Kinase Abl and Its Substrate Enabled Collaborate with the Receptor Phosphatase Dlar to Control Motor Axon Guidance

Wills, Zachary P.; Bateman, Jack R.; Korey, Christopher A.; Comer, Allen R.; Vactor, David Van

doi:10.1016/s0896-6273(00)81091-0

Cited by 276 publications

(246 citation statements)

References 68 publications

(1 reference statement)

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“…Drosophila contain a single Abl family kinase, Abl, which is equally related to Abl and Arg phylogenetically. Drosophila Abl localizes to cell-cell contact points (Bennett and Hoffmann, 1992), and loss of its function leads to defects in epithelial cell morphogenesis (Grevengoed et al, 2001(Grevengoed et al, , 2003 and axon guidance (Wills et al, 1999a(Wills et al, ,b, 2002Bashaw et al, 2000;Liebl et al, 2000). Our results suggest that these phenotypes may result in part from a failure to properly regulate actomyosin contractility.…”

Section: Arg Is a New Important Regulator Of Fas In Migrating Cellsmentioning

confidence: 63%

The Abl-related Gene Tyrosine Kinase Acts through p190RhoGAP to Inhibit Actomyosin Contractility and Regulate Focal Adhesion Dynamics upon Adhesion to Fibronectin

Peacock

Miller

Bradley

et al. 2007

MBoC

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In migrating cells, actin polymerization promotes protrusion of the leading edge, whereas actomyosin contractility powers net cell body translocation. Although they promote F-actin-dependent protrusions of the cell periphery upon adhesion to fibronectin (FN), Abl family kinases inhibit cell migration on FN. We provide evidence here that the Abl-related gene (Arg/Abl2) kinase inhibits fibroblast migration by attenuating actomyosin contractility and regulating focal adhesion dynamics. arg؊/؊ fibroblasts migrate at faster average speeds than wild-type (wt) cells, whereas Arg re-expression in these cells slows migration. Surprisingly, the faster migrating arg؊/؊ fibroblasts have more prominent F-actin stress fibers and focal adhesions and exhibit increased actomyosin contractility relative to wt cells. Interestingly, Arg requires distinct functional domains to inhibit focal adhesions and actomyosin contractility. The kinase domain-containing Arg N-terminal half can act through the RhoA inhibitor p190RhoGAP to attenuate stress fiber formation and cell contractility. However, Arg requires both its kinase activity and its cytoskeleton-binding C-terminal half to fully inhibit focal adhesions. Although focal adhesions do not turn over efficiently in the trailing edge of arg؊/؊ cells, the increased contractility of arg؊/؊ cells tears the adhesions from the substrate, allowing for the faster migration observed in these cells. Together, our data strongly suggest that Arg inhibits cell migration by restricting actomyosin contractility and regulating its coupling to the substrate through focal adhesions.

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Section: Arg Is a New Important Regulator Of Fas In Migrating Cellsmentioning

confidence: 63%

The Abl-related Gene Tyrosine Kinase Acts through p190RhoGAP to Inhibit Actomyosin Contractility and Regulate Focal Adhesion Dynamics upon Adhesion to Fibronectin

Peacock

Miller

Bradley

et al. 2007

MBoC

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“…It is unclear how LAR and other RPTPs signal within the cell to induce the cytoskeletal rearrangements that mediate these functions. Trio, a guanine nucleotide exchange factor for Rac (15), and Enabled (Ena), which regulates actin polymerization (16), show genetic interactions with LAR in both R7 targeting (8) and motor axon guidance (17). LAR can dephosphorylate both Ena and its antagonist, the cytoplasmic kinase Abelson (Abl) (17).…”

mentioning

confidence: 99%

“…Trio, a guanine nucleotide exchange factor for Rac (15), and Enabled (Ena), which regulates actin polymerization (16), show genetic interactions with LAR in both R7 targeting (8) and motor axon guidance (17). LAR can dephosphorylate both Ena and its antagonist, the cytoplasmic kinase Abelson (Abl) (17). Yeast two-hybrid screens for proteins that bind to the LAR intracellular domain identified both the human and Drosophila homologues of Liprin-␣, a protein with an N-terminal coiled-coil domain and a C-terminal LAR-binding liprin homology domain (LHD) consisting of three sterile alpha motif domains (12,18).…”

mentioning

confidence: 99%

Liprin-α has LAR-independent functions in R7 photoreceptor axon targeting

Hofmeyer

Maurel-Zaffran

Sink

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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In the Drosophila visual system, the color-sensing photoreceptors R7 and R8 project their axons to two distinct layers in the medulla. Loss of the receptor tyrosine phosphatase LAR from R7 photoreceptors causes their axons to terminate prematurely in the R8 layer. Here we identify a null mutation in the Liprin-␣ gene based on a similar R7 projection defect. Liprin-␣ physically interacts with the inactive D2 phosphatase domain of LAR, and this domain is also essential for R7 targeting. However, another LAR-dependent function, egg elongation, requires neither Liprin-␣ nor the LAR D2 domain. Although human and Caenorhabditis elegans Liprin-␣ proteins have been reported to control the localization of LAR, we find that LAR localizes to focal adhesions in Drosophila S2R؉ cells and to photoreceptor growth cones in vivo independently of Liprin-␣. In addition, Liprin-␣ overexpression or loss of function can affect R7 targeting in the complete absence of LAR. We conclude that Liprin-␣ does not simply act by regulating LAR localization but also has LAR-independent functions. receptor tyrosine phosphatase ͉ visual system ͉ Drosophila T he color-sensitive photoreceptors of the Drosophila visual system, R7 and R8, provide a simple system in which to study layer-specific axon targeting. Whereas the outer photoreceptors R1-R6 project their axons to the lamina, R7 and R8 project to the medulla, where R8 terminates in the more superficial M3 layer and R7 in the deeper M6 layer. This targeting occurs in two stages, with both R7 and R8 growth cones pausing in separate temporary layers before proceeding to their final positions (1). Several genes are known to contribute to the establishment of the R7 and R8 projection pattern. The transcription factor Runt is expressed in R7 and R8, and its misexpression is sufficient to target R2 and R5 to the medulla, suggesting that it controls the choice of optic neuropil (2). Endogenous expression of the homophilic cell adhesion molecule Capricious (Caps) in R8 or its ectopic expression in R7 directs these photoreceptors to terminate in the Caps-positive M3 layer (3). The transmembrane cadherin Flamingo (Fmi) is required for R8 targeting (4, 5), whereas loss of either N-cadherin (Ncad) (6) or one of the receptor protein tyrosine phosphatases (RPTPs), PTP69D (7) or LAR (8, 9), causes R7 to terminate inappropriately in the R8 layer.Other functions of LAR include axonal patterning of photoreceptors R1-R6 (9) and embryonic motor neurons (10, 11), synapse morphogenesis at the larval neuromuscular junction (NMJ) (12), and polarization of actin filaments in the follicle cells surrounding the oocyte, which promotes egg elongation along the anterior-posterior axis (13,14). It is unclear how LAR and other RPTPs signal within the cell to induce the cytoskeletal rearrangements that mediate these functions. Trio, a guanine nucleotide exchange factor for Rac (15), and Enabled (Ena), which regulates actin polymerization (16), show genetic interactions with LAR in both R7 targeting (8) and motor axon guidance ...

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“…6, C and D). To confirm that the reduction in neuronal survival observed after pharmacological inhibition of Arg/Abl involved a reduction in IB-␤ phosphorylation, we performed 32 P metabolic labeling experiments. IB-␤ was immunoprecipitated from lysates of neuronal cultures that were labeled with 32 P and treated with PD173955.…”

Section: Abl Inhibitors Induce Apoptosis In Hk Condition and Reduce Imentioning

confidence: 99%

Phosphorylation of IκB-β Is Necessary for Neuronal Survival

Liu

D’Mello

2006

Journal of Biological Chemistry

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Cerebellar granule neurons undergo apoptosis when switched from culture medium containing depolarizing levels of potassium (high potassium or HK) to nondepolarizing medium (low potassium or LK). We showed that in healthy neurons maintained in HK medium, IB-␤ is phosphorylated at a novel site, Tyr-161. LK-induced neuronal apoptosis is accompanied by a decrease in the extent of IB-␤ phosphorylation at this residue. Tyr-161 shares similarity to the consensus sequence for phosphorylation by the nonreceptor tyrosine kinases Abl and Arg. Arg phosphorylates Tyr-161 differentially in vitro, and LK treatment does cause a downregulation of Arg activity. Moreover, treatment of neurons with two structurally distinct and highly selective Abl inhibitors, PD173955 and Gleevec, blocks HK-induced phosphorylation of IB-␤ at Tyr-161 and induces neuronal apoptosis. Overexpression of wild-type IB-␤ blocks LK-induced apoptosis, but this effect is abolished when Arg is pharmacologically inhibited. On the other hand, forced overexpression of IB-␤ in which Tyr-161 is mutated inhibits survival in HK demonstrating the importance of this residue to neuronal survival. Phosphorylation of IB-␤ enhances its association with p65/RelA causing an increase in NF-B DNA binding activity. Our results identified IB-␤ phosphorylation as a key event in neuronal survival and provided a mechanism by which this is mediated.Apoptosis plays a critical role in the normal development of the nervous system by eliminating large numbers of superfluous neurons and ensuring proper neural connections. Aberrant apoptosis often occurs during adulthood leading to an unwanted loss of neurons such as that seen in neuropathological conditions, including Alzheimer, Parkinson, or Huntington disease and following ischemic stroke (reviewed in Ref.

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The Tyrosine Kinase Abl and Its Substrate Enabled Collaborate with the Receptor Phosphatase Dlar to Control Motor Axon Guidance

Cited by 276 publications

References 68 publications

The Abl-related Gene Tyrosine Kinase Acts through p190RhoGAP to Inhibit Actomyosin Contractility and Regulate Focal Adhesion Dynamics upon Adhesion to Fibronectin

The Abl-related Gene Tyrosine Kinase Acts through p190RhoGAP to Inhibit Actomyosin Contractility and Regulate Focal Adhesion Dynamics upon Adhesion to Fibronectin

Liprin-α has LAR-independent functions in R7 photoreceptor axon targeting

Phosphorylation of IκB-β Is Necessary for Neuronal Survival

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