Paxillin phosphorylation counteracts proteoglycan-mediated inhibition of axon regeneration

Kuboyama, Tomoharu; Luo, Xueting; Park, Kevin; Blackmore, Murray G.; Tojima, Takuro; Tohda, Chihiro; Bixby, John L.; Lemmon, Vance; Kamiguchi, Hiroyuki

doi:10.1016/j.expneurol.2013.06.011

Cited by 13 publications

(7 citation statements)

References 64 publications

(88 reference statements)

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“…This might explain the observed upregulation of aggrecan in the ischemic optic nerve. As shown recently, aggrecan inhibits growth of axonal fibers in an optic nerve crush model in vivo 70. Therefore, under ischemic conditions, aggrecan represents a favorable candidate that inhibits axonal regeneration.…”

Section: Discussionmentioning

confidence: 63%

Ischemic injury leads to extracellular matrix alterations in retina and optic nerve

Reinhard

Renner

Wiemann

et al. 2017

Sci Rep

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Retinal ischemia occurs in a variety of eye diseases. Restrained blood flow induces retinal damage, which leads to progressive optic nerve degeneration and vision loss. Previous studies indicate that extracellular matrix (ECM) constituents play an important role in complex tissues, such as retina and optic nerve. They have great impact on de- and regeneration processes and represent major candidates of central nervous system glial scar formation. Nevertheless, the importance of the ECM during ischemic retina and optic nerve neurodegeneration is not fully understood yet. In this study, we analyzed remodeling of the extracellular glycoproteins fibronectin, laminin, tenascin-C and tenascin-R and the chondroitin sulfate proteoglycans (CSPGs) aggrecan, brevican and phosphacan/RPTPβ/ζ in retinae and optic nerves of an ischemia/reperfusion rat model via quantitative real-time PCR, immunohistochemistry and Western blot. A variety of ECM constituents were dysregulated in the retina and optic nerve after ischemia. Regarding fibronectin, significantly elevated mRNA and protein levels were observed in the retina following ischemia, while laminin and tenascin-C showed enhanced immunoreactivity in the optic nerve after ischemia. Interestingly, CSPGs displayed significantly increased expression levels in the optic nerve. Our study demonstrates a dynamic expression of ECM molecules following retinal ischemia, which strengthens their regulatory role during neurodegeneration.

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Section: Discussionmentioning

confidence: 63%

Ischemic injury leads to extracellular matrix alterations in retina and optic nerve

Reinhard

Renner

Wiemann

et al. 2017

Sci Rep

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“…The failure of axon growth on CSPGs has recently been attributed to the activation of protein kinase A (PKA) (214). These data are interesting as cAMP, which activates PKA, is known to promote regeneration of optic nerves (216,269).…”

Section: B Chondroitin Sulfate Proteoglycans Mediate Signaling In Thmentioning

confidence: 99%

The Biology of Regeneration Failure and Success After Spinal Cord Injury

Tran

Warren

Silver

2018

Physiological Reviews

590

557

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Since no approved therapies to restore mobility and sensation following spinal cord injury (SCI) currently exist, a better understanding of the cellular and molecular mechanisms following SCI that compromise regeneration or neuroplasticity is needed to develop new strategies to promote axonal regrowth and restore function. Physical trauma to the spinal cord results in vascular disruption that, in turn, causes blood-spinal cord barrier rupture leading to hemorrhage and ischemia, followed by rampant local cell death. As subsequent edema and inflammation occur, neuronal and glial necrosis and apoptosis spread well beyond the initial site of impact, ultimately resolving into a cavity surrounded by glial/fibrotic scarring. The glial scar, which stabilizes the spread of secondary injury, also acts as a chronic, physical, and chemo-entrapping barrier that prevents axonal regeneration. Understanding the formative events in glial scarring helps guide strategies towards the development of potential therapies to enhance axon regeneration and functional recovery at both acute and chronic stages following SCI. This review will also discuss the perineuronal net and how chondroitin sulfate proteoglycans (CSPGs) deposited in both the glial scar and net impede axonal outgrowth at the level of the growth cone. We will end the review with a summary of current CSPG-targeting strategies that help to foster axonal regeneration, neuroplasticity/sprouting, and functional recovery following SCI.

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“…In support of this assumption, the deletion of the paxillin gene in mouse embryos is lethal. Specifically, phosphorylation of paxillin by PAK (kinase activated by p21) at Ser273 in the chick (Ser272 in human) has been shown to promote the adhesion and migration of non-neural cells [ 88 ]. Also, in this line, the activity of dipeptidyl peptidase IV family protease (DPP9) has been shown to be essential for mice neonatal survival.…”

Section: Paxillin Function In Specific Cells and Tissuesmentioning

confidence: 99%

Paxillin: a crossroad in pathological cell migration

et al. 2017

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Paxilllin is a multifunctional and multidomain focal adhesion adapter protein which serves an important scaffolding role at focal adhesions by recruiting structural and signaling molecules involved in cell movement and migration, when phosphorylated on specific Tyr and Ser residues. Upon integrin engagement with extracellular matrix, paxillin is phosphorylated at Tyr31, Tyr118, Ser188, and Ser190, activating numerous signaling cascades which promote cell migration, indicating that the regulation of adhesion dynamics is under the control of a complex display of signaling mechanisms. Among them, paxillin disassembly from focal adhesions induced by extracellular regulated kinase (ERK)-mediated phosphorylation of serines 106, 231, and 290 as well as the binding of the phosphatase PEST to paxillin have been shown to play a key role in cell migration. Paxillin also coordinates the spatiotemporal activation of signaling molecules, including Cdc42, Rac1, and RhoA GTPases, by recruiting GEFs, GAPs, and GITs to focal adhesions. As a major participant in the regulation of cell movement, paxillin plays distinct roles in specific tissues and developmental stages and is involved in immune response, epithelial morphogenesis, and embryonic development. Importantly, paxillin is also an essential player in pathological conditions including oxidative stress, inflammation, endothelial cell barrier dysfunction, and cancer development and metastasis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0418-y) contains supplementary material, which is available to authorized users.

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Paxillin phosphorylation counteracts proteoglycan-mediated inhibition of axon regeneration

Cited by 13 publications

References 64 publications

Ischemic injury leads to extracellular matrix alterations in retina and optic nerve

Ischemic injury leads to extracellular matrix alterations in retina and optic nerve

The Biology of Regeneration Failure and Success After Spinal Cord Injury

Paxillin: a crossroad in pathological cell migration

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