Atypical Protein Kinase C and Par3 Are Required for Proteoglycan-Induced Axon Growth Inhibition

Lee, Seong-il; Zhang, Weibing; Ravi, Mayuri; Weschenfelder, Markus; Bastmeyer, Martin; Levine, Joel M.

doi:10.1523/jneurosci.3154-12.2013

Cited by 22 publications

(14 citation statements)

References 75 publications

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“…These experiments indicate that the PKCζ isoform contributes to LAR action upon CSPG application, probably by regulating LKB1 activity. Similarly, application of NG2, a non-lectican CSPG that is normally membrane-bound, regulated PKCζ activity in rat postnatal neurons and contributed to axon growth inhibition by NG262. Because PKC appears to mediate actions of some axon growth inhibitors63, we also examined PKC activity by measuring levels of p-PKC-pan.…”

Section: Resultsmentioning

confidence: 99%

Two PTP receptors mediate CSPG inhibition by convergent and divergent signaling pathways in neurons

Ohtake

Wong

Abdul-Muneer

et al. 2016

Sci Rep

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Receptor protein tyrosine phosphatase σ (PTPσ) and its subfamily member LAR act as transmembrane receptors that mediate growth inhibition of chondroitin sulfate proteoglycans (CSPGs). Inhibition of either receptor increases axon growth into and beyond scar tissues after CNS injury. However, it is unclear why neurons express two similar CSPG receptors, nor whether they use the same or different intracellular pathways. We have now studied the signaling pathways of these two receptors using N2A cells and primary neurons derived from knockout mice. We demonstrate that both receptors share certain signaling pathways (RhoA, Akt and Erk), but also use distinct signals to mediate CSPG actions. Activation of PTPσ by CSPGs selectively inactivated CRMP2, APC, S6 kinase and CREB. By contrast LAR activation inactivated PKCζ, cofilin and LKB1. For the first time, we propose a model of the signaling pathways downstream of these two CSPG receptors. We also demonstrate that deleting both receptors exhibits additive enhancement of axon growth in adult neuronal cultures in vitro. Our findings elucidate the novel downstream pathways of CSPGs and suggest potential synergy of blocking their two PTP receptors.

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Section: Resultsmentioning

confidence: 99%

Two PTP receptors mediate CSPG inhibition by convergent and divergent signaling pathways in neurons

Ohtake

Wong

Abdul-Muneer

et al. 2016

Sci Rep

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“…NG2 also signals to RhoA by interaction with a number of CSPG receptors such as Protein Tyrosine Phosphatase σ (PTPσ), NgR1, and NgR3 (reviewed in Ohtake and Shuxin, 2015). Additional mechanisms of NG2-mediated growth inhibition exist such as signaling through Cdc42 and atypical protein kinase C (PKCζ), which alters Par complex function (Lee et al, 2013).…”

Section: Molecular Mechanisms Of Glial Cell-axonal Growth Cone Interamentioning

confidence: 99%

Glial Cell-Axonal Growth Cone Interactions in Neurodevelopment and Regeneration

2020

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The developing nervous system is a complex yet organized system of neurons, glial support cells, and extracellular matrix that arranges into an elegant, highly structured network. The extracellular and intracellular events that guide axons to their target locations have been well characterized in many regions of the developing nervous system. However, despite extensive work, we have a poor understanding of how axonal growth cones interact with surrounding glial cells to regulate network assembly. Gliato-growth cone communication is either direct through cellular contacts or indirect through modulation of the local microenvironment via the secretion of factors or signaling molecules. Microglia, oligodendrocytes, astrocytes, Schwann cells, neural progenitor cells, and olfactory ensheathing cells have all been demonstrated to directly impact axon growth and guidance. Expanding our understanding of how different glial cell types directly interact with growing axons throughout neurodevelopment will inform basic and clinical neuroscientists. For example, identifying the key cellular players beyond the axonal growth cone itself may provide translational clues to develop therapeutic interventions to modulate neuron growth during development or regeneration following injury. This review will provide an overview of the current knowledge about glial involvement in development of the nervous system, specifically focusing on how glia directly interact with growing and maturing axons to influence neuronal connectivity. This focus will be applied to the clinically-relevant field of regeneration following spinal cord injury, highlighting how a better understanding of the roles of glia in neurodevelopment can inform strategies to improve axon regeneration after injury.

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“…More recently, these presumptive signal transduction pathways have been proposed to involve activation of PKCz and the polarity complex proteins Par3 and Par6 [also known as partitioning defective homologue 3/6 (PARD3/PARD6)]. (Table 1), leading to downstream activation of Rac family small GTPase 1and cdc42 (94). Notwithstanding that GPCRs are documented to be involved in chemorepulsive phenomena, the identity of the proposed neuronal NG2/CSPG4 receptor and the modes through which its ligand interaction would activate intracellular signaling events remains veiled.…”

Section: Permissive Vs Nonpermissive Molecular Interactions Of Ng2/cmentioning

confidence: 99%

Structural deciphering of the NG2/CSPG4 proteoglycan multifunctionality

et al. 2018

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The chondroitin sulfate proteoglycan 4 (CSPG4) gene encodes a transmembrane proteoglycan (PG) constituting the largest and most structurally complex macromolecule of the human surf aceome. Its transcript shows an extensive evolutionary conservation and, due to the elaborated intracellular processing of the translated protein, it generates an array of glycoforms with the potential to exert variant‐specific functions. CSPG4‐mediated molecular events are articulated through the interaction with more than 40 putative ligands and the concurrent involvement of the ectodomain and cytoplasmic tail. Alternating inside‐out and outside‐in signal transductions may thereby be elicited through a tight functional connection of the PG with the cytoskeleton and its regulators. The potential of CSPG4 to influence both types of signaling mechanisms is also asserted by its lateral mobility along the plasma membrane and its intersection with microdomain‐restricted internalization and endocytic trafficking. Owing to the multitude of molecular interplays that CSPG4 may engage, and thanks to a differential phosphorylation of its intracellular domain accounted by crosstalking signaling pathways, the PG stands out for its unique capability to affect numerous cellular phenomena, including those purporting pathologic conditions. We discuss here the progresses made in advancing our understanding about the structural‐functional bases for the ability of CSPG4 to widely impact on cell behavior, such as to highlight how its multivalency may be exploited to interfere with disease progression.—Tamburini, E., Dallatomasina, A., Quartararo, J., Cortelazzi, B., Mangieri, D., Lazzaretti, M., Perris, R. Structural deciphering of the NG2/CSPG4 proteoglycan multifunctionality. FASEB J. 33, 3112–3128 (2019). http://www.fasebj.org

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Atypical Protein Kinase C and Par3 Are Required for Proteoglycan-Induced Axon Growth Inhibition

Cited by 22 publications

References 75 publications

Two PTP receptors mediate CSPG inhibition by convergent and divergent signaling pathways in neurons

Two PTP receptors mediate CSPG inhibition by convergent and divergent signaling pathways in neurons

Glial Cell-Axonal Growth Cone Interactions in Neurodevelopment and Regeneration

Structural deciphering of the NG2/CSPG4 proteoglycan multifunctionality

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