The Fer tyrosine kinase regulates an axon retraction response to Semaphorin 3A in dorsal root ganglion neurons

Shapovalova, Zoya; Tabunshchyk, K. V.; Greer, Peter A.

doi:10.1186/1471-213x-7-133

Cited by 25 publications

(17 citation statements)

References 56 publications

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“…S3). Together with previous reports that overexpression of Fer caused death of non-neuronal cells and inhibited axonal outgrowth in neurons (41,42), our studies strongly suggest that Fer interaction with NRP1 may lead to neuronal death. FIGURE 6.…”

Section: Fer Directly and Selectively Interacts With Nrp1 In Ischemicsupporting

confidence: 88%

Neuropilin 1 Directly Interacts with Fer Kinase to Mediate Semaphorin 3A-induced Death of Cortical Neurons

Jiang¹,

Whitehead²,

Aylsworth

et al. 2010

Journal of Biological Chemistry

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Neuropilins (NRPs) are receptors for the major chemorepulsive axonal guidance cue semaphorins (Sema). The interaction of Sema3A/NRP1 during development leads to the collapse of growth cones. Here we show that Sema3A also induces death of cultured cortical neurons through NRP1. A specific NRP1 inhibitory peptide ameliorated Sema3A-evoked cortical axonal retraction and neuronal death. Moreover, Sema3A was also involved in cerebral ischemia-induced neuronal death. Expression levels of Sema3A and NRP1, but not NRP2, were significantly increased early during brain reperfusion following transient focal cerebral ischemia. NRP1 inhibitory peptide delivered to the ischemic brain was potently neuroprotective and prevented the loss of motor functions in mice. The integrity of the injected NRP1 inhibitory peptide into the brain remained unchanged, and the intact peptide permeated the ischemic hemisphere of the brain as determined using MALDI-MS-based imaging. Mechanistically, NRP1-mediated axonal collapse and neuronal death is through direct and selective interaction with the cytoplasmic tyrosine kinase Fer. Fer RNA interference effectively attenuated Sema3A-induced neurite retraction and neuronal death in cortical neurons. More importantly, down-regulation of Fer expression using Fer-specific RNA interference attenuated cerebral ischemia-induced brain damage. Together, these studies revealed a previously unknown function of NRP1 in signaling Sema3A-evoked neuronal death through Fer in cortical neurons.Injured central nervous system axons have a very limited capacity to regenerate due to the presence of a plethora of growth inhibitory ligands secreted from oligodendrocytes/myelin, reactive astrocytes, and fibroblasts in the damaged tissue (1-6). Neurons must integrate this multitude of inhibitory molecular cues, generated as a result of cortical damage, into a functional response. More often than not the response is one of growth cone collapse, axonal retraction, and neuronal death. Therefore, chemorepulsive factors likely contribute either directly or indirectly to neuronal death in the injured adult brain (7-10). Indeed, the expression of Sema3A, a major chemorepulsive factor, has been reported in several brain injury models, such as peripheral nerve injury, spinal cord injury, cerebral ischemia, and Alzheimer disease (1, 3, 11-16). In addition, Sema3A expression has been shown to increase vascular permeability, which may indirectly contribute to neuronal damage (17).The biological activities of Sema3A during development are complex and context-dependent. Although best known for its role as an axonal growth cone repellent, Sema3A also serves as a chemoattractant during cortical layer development by guiding the radial migration of layer II/III cortical neurons (18) and the growth of apical dendrites toward the pial surface (19). In contrast, Sema3A is also important in stereotyped pruning of long hippocampal axon branches (20), causing dorsal root ganglia axon retraction (21), and evoking apoptosis of sensory neurons (22-2...

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Section: Fer Directly and Selectively Interacts With Nrp1 In Ischemicsupporting

confidence: 88%

Neuropilin 1 Directly Interacts with Fer Kinase to Mediate Semaphorin 3A-induced Death of Cortical Neurons

Jiang¹,

Whitehead²,

Aylsworth

et al. 2010

Journal of Biological Chemistry

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“…This suggests a pathway from Sema 3A to CRMP through Fes, however the exact residues targeted by the tyrosine kinase remain to be determined, along with the stoichiometry of phosphorylation or the effect of mutation of the targeted tyrosine. In addition, the Fes related kinase Fer, can phosphorylate CRMP2 in vitro and is regulated by Sema 3A [35], but again the exact details of the phosphorylation are not known. Interestingly, Fes/Fps/Fer may actually lie downstream of CRMP2, since their activity can be reduced by expression of CRMP2 [35].…”

Section: Regulationmentioning

confidence: 97%

“…In addition, the Fes related kinase Fer, can phosphorylate CRMP2 in vitro and is regulated by Sema 3A [35], but again the exact details of the phosphorylation are not known. Interestingly, Fes/Fps/Fer may actually lie downstream of CRMP2, since their activity can be reduced by expression of CRMP2 [35]. The phosphorylation of CRMP5 may mediate its interaction with the neuronal glycine transporter GlyT2, since phosphatase inhibitors increase the complex formation in cells [36].…”

Section: Regulationmentioning

confidence: 97%

Increased CRMP2 Phosphorylation is Observed in Alzheimers Disease; Does this Tell us Anything About Disease Development?

Soutar¹,

Thornhill²,

Cole³

et al. 2009

CAR

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Collapsin response mediator protein-2 (CRMP2) was recently identified as a physiological substrate for GSK3 and Cdk5, two protein kinases suggested to exhibit greater activity in Alzheimer's disease (AD). Indeed, phosphorylation of CRMP2, at the residues targeted by GSK3 and Cdk5, is relatively high in cortex isolated from human AD brain, as well as in the brains of animal models of AD, while phospho-CRMP2 is found in neurofibrillary tangles. In mouse models of AD, increased phosphorylation occurs prior to pathology. Although CRMP2 has no known enzymatic activity, a great deal of information is appearing on its importance in neuronal development and polarity, as well as in axon growth and guidance. In this mini-review, we examine what is known about CRMP2 function, how that is controlled by phosphorylation, what alterations in molecular mechanisms could lead to the abnormally high CRMP2 phosphorylation in AD, and whether this is likely to be specific to AD or occur in other forms of neurodegeneration. This will include discussion of the evidence for increased GSK3 or Cdk5 activity, for decreased phosphatase activity, or the upregulation of other CRMP2 protein kinases in AD. Importantly, we will compare the processes that may contribute to increased CRMP2 phosphorylation with those known to increase tau hyperphosphorylation in AD, and whether these are likely to be part of disease development or a useful early marker for AD.

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“…Secondly, Fyn, which is activated by associating with PlexinA1, activates another kinase, Cdk5, which then phosphorylates CRMP2 [25, 26]. Finally, Fer and Fes, which binds PlexinA1 and directly phosphorylate CRMP2 after Sema3A treatment [27, 28] (Figure 2A). For information about additional Sema3A signaling pathways in neurons, see the review by Tran and colleagues [7].…”

Section: Semaphorinsmentioning

confidence: 99%

Guidance from above: common cues direct distinct signaling outcomes in vascular and neural patterning

Gelfand

Hong

2009

Trends in Cell Biology

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The nervous and vascular systems are both exquisitely branched and complicated systems and their proper development requires careful guidance of nerves and vessels. The recent realization that common ligand-receptor pairs are used in guiding the patterning of both systems has prompted the question of whether similar signaling pathways are used in both systems. This review highlights recent progress in our understanding of the similarities and differences in the intracellular signaling mechanisms downstream of semaphorins, ephrins, and VEGF in neurons and endothelial cells during neural and vascular development. We present evidence that similar intracellular signaling principles underlying cytoskeletal regulation are used to control neural and vascular guidance, while the specific molecules used in neurons and endothelial cells are often different.

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The Fer tyrosine kinase regulates an axon retraction response to Semaphorin 3A in dorsal root ganglion neurons

Cited by 25 publications

References 56 publications

Neuropilin 1 Directly Interacts with Fer Kinase to Mediate Semaphorin 3A-induced Death of Cortical Neurons

Neuropilin 1 Directly Interacts with Fer Kinase to Mediate Semaphorin 3A-induced Death of Cortical Neurons

Increased CRMP2 Phosphorylation is Observed in Alzheimers Disease; Does this Tell us Anything About Disease Development?

Guidance from above: common cues direct distinct signaling outcomes in vascular and neural patterning

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