Metastasis-associated Mts1 (S100A4) protein is selectively expressed in white matter astrocytes and is up-regulated after peripheral nerve or dorsal root injury

Kozlova, Elena N.; Lukanidin, Eugene

doi:10.1002/(sici)1098-1136(199909)27:3<249::aid-glia6>3.0.co;2-e

Cited by 51 publications

(35 citation statements)

References 25 publications

(27 reference statements)

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“…However, expression of the protein has been demonstrated in a variety of neural cells, and it is strongly increased after brain traumas and nerve lesions (25,34). Moreover, secretion of S100A4 in vitro has been reported, with the concentration of the secreted protein in the culture medium estimated to be about 10 M (10), which is comparable with the S100A4 concentrations used in this study.…”

Section: Discussionsupporting

confidence: 78%

“…In both the brain and spinal cord, S100A4 expression appears in astrocytes shortly after the start of myelination, with the highest level observed in the areas in which neurogenesis takes place and in regions possessing high plasticity in adults (1). Moreover, in the peripheral nervous system, expression of S100A4 increases after sciatic nerve or dorsal root injury (25). Thus, the release of S100A4 from S100A4-positive astrocytes as a result of either secretion or cell damage might play a role in neuronal plasticity under normal and pathological conditions.…”

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confidence: 99%

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Molecular Mechanisms of Ca²⁺ Signaling in Neurons Induced by the S100A4 Protein

Kiryushko¹,

Novitskaya²,

Soroka³

et al. 2006

Molecular and Cellular Biology

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The S100A4 protein belongs to the S100 family of vertebrate-specific proteins possessing both intra-and extracellular functions. In the nervous system, high levels of S100A4 expression are observed at sites of neurogenesis and lesions, suggesting a role of the protein in neuronal plasticity. Extracellular oligomeric S100A4 is a potent promoter of neurite outgrowth and survival from cultured primary neurons; however, the molecular mechanism of this effect has not been established. Here we demonstrate that oligomeric S100A4 increases the intracellular calcium concentration in primary neurons. We present evidence that both S100A4-induced Ca 2؉ signaling and neurite extension require activation of a cascade including a heterotrimeric G protein(s), phosphoinositide-specific phospholipase C, and diacylglycerol-lipase, resulting in Ca 2؉ entry via nonselective cation channels and via T-and L-type voltage-gated Ca 2؉ channels. We demonstrate that S100A4-induced neurite outgrowth is not mediated by the receptor for advanced glycation end products, a known target for other extracellular S100 proteins. However, S100A4-induced signaling depends on interactions with heparan sulfate proteoglycans at the cell surface. Thus, glycosaminoglycans may act as coreceptors of S100 proteins in neurons. This may provide a mechanism by which S100 proteins could locally regulate neuronal plasticity in connection with brain lesions and neurological disorders.The S100 family is a group of vertebrate-specific Ca 2ϩ -binding proteins with a highly conserved primary structure possessing both intra-and extracellular functions. Most S100 family members, including S100A4, are antiparallelly packed homodimers stabilized by disulfide bridges (reviewed in references 8 and 9). Intracellularly, S100 proteins are involved in a variety of processes, including the regulation of cytoskeletal dynamics, Ca 2ϩ homeostasis, and cell proliferation and differentiation. Importantly, some S100 proteins can also be secreted, form oligomers owing to the nonreducing conditions of the environment, and exert their effects acting at the cell surface (10; 43; reviewed in reference 20). A plasma membrane target for S100B and S100A12, the receptor for advanced glycation end products (RAGE), has been identified on inflammatory and neural cells (14). However, RAGE is probably not the sole receptor for members of the S100 family, since the effects of extracellular S100A12 and S100B proteins can be observed in cells lacking RAGE (32), and some of these effects are RAGE independent in cells expressing the receptor (37).The S100A4 (also termed Mts1) gene was isolated from tumor cells (11,40), where its expression increased the ability of the tumor to metastasize. S100A4 has also been detected in healthy tissues, particularly in the nervous system. In both the brain and spinal cord, S100A4 expression appears in astrocytes shortly after the start of myelination, with the highest level observed in the areas in which neurogenesis takes place and in regions possessing high plasticit...

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Section: Discussionsupporting

confidence: 78%

mentioning

confidence: 99%

Molecular Mechanisms of Ca²⁺ Signaling in Neurons Induced by the S100A4 Protein

Kiryushko¹,

Novitskaya²,

Soroka³

et al. 2006

Molecular and Cellular Biology

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125

123

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“…5A) as previously described in the human adult brain (2). However, S100A16 transcript levels were ten times higher when compared with S100A4 mRNA levels, a S100 protein involved in neuronal differentiation as well as in the response of astrocytes to degeneration of myelinated axons (52,53). Moreover, as reported for other members of the S100 protein family, brain expression gradually decreases with age (54).…”

Section: Discussionsupporting

confidence: 63%

S100A16, a Novel Calcium-binding Protein of the EF-hand Superfamily

Sturchler

Cox

Durussel

et al. 2006

Journal of Biological Chemistry

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S100A16 protein is a new and unique member of the EF-hand Ca2؉ -binding proteins. S100 proteins are cell-and tissue-specific and are involved in many intra-and extracellular processes through interacting with specific target proteins. In the central nervous system S100 proteins are implicated in cell proliferation, differentiation, migration, and apoptosis as well as in cognition. S100 proteins became of major interest because of their close association with brain pathologies, for example depression or Alzheimer's disease. Here we report for the first time the purification and biochemical characterization of human and mouse recombinant S100A16 proteins. Flow dialysis revealed that both homodimeric S100A16 proteins bind two Ca 2؉ ions with the C-terminal EF-hand of each subunit, the human protein exhibiting a 2-fold higher affinity. Trp fluorescence variations indicate conformational changes in the orthologous proteins upon Ca 2؉ binding, whereas formation of a hydrophobic patch, implicated in target protein recognition, only occurs in the human S100A16 protein. In situ hybridization analysis and immunohistochemistry revealed a widespread distribution in the mouse brain. Furthermore, S100A16 expression was found to be astrocyte-specific. Finally, we investigated S100A16 intracellular localization in human glioblastoma cells. The protein was found to accumulate within nucleoli and to translocate to the cytoplasm in response to Ca 2؉ stimulation.

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“…Moreover, similarity exists between the patterns of S100A4 expression in the CNS and PNS, where the protein is detected in astrocytes and Schwann cells, respectively, and is strongly upregulated after injury (9,17,18). Accordingly, here we found that S100A4 was expressed by Schwann cells and selected axons in the sciatic nerves of both wild-type and P 0 -/-mice ( Figure 6).…”

Section: Discussionsupporting

confidence: 65%

“…Although S100A4 has been less investigated in the peripheral nervous system (PNS) than in the CNS, several studies indicate that its expression also increases in myelinating Schwann cells and/or unmyelinating Remak bundles at the injury site after dorsal root or peripheral nerve injury (17,18). Increased S100A4 levels after injury were also found in a subpopulation of neurons, mainly sensory and autonomic (18).…”

Section: Introductionmentioning

confidence: 99%

Peptide Mimetic of the S100A4 Protein Modulates Peripheral Nerve Regeneration and Attenuates the Progression of Neuropathy in Myelin Protein P0 Null Mice

Moldovan

Pinchenko

Dmytriyeva

et al. 2013

Mol Med

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We recently found that S100A4, a member of the multifunctional S100 protein family, protects neurons in the injured brain and identified two sequence motifs in S100A4 mediating its neurotrophic effect. Synthetic peptides encompassing these motifs stimulated neuritogenesis and survival in vitro and mimicked the S100A4-induced neuroprotection in brain trauma. Here, we investigated a possible function of S100A4 and its mimetics in the pathologies of the peripheral nervous system (PNS). We found that S100A4 was expressed in the injured PNS and that its peptide mimetic (H3) affected the regeneration and survival of myelinated axons. H3 accelerated electrophysiological, behavioral and morphological recovery after sciatic nerve crush while transiently delaying regeneration after sciatic nerve transection and repair. On the basis of the finding that both S100A4 and H3 increased neurite branching in vitro, these effects were attributed to the modulatory effect of H3 on initial axonal sprouting. In contrast to the modest effect of H3 on the time course of regeneration, H3 had a long-term neuroprotective effect in the myelin protein P0 nul mice, a model of dysmyelinating neuropathy (Charcot-Marie-Tooth type 1 disease), where the peptide attenuated the deterioration of nerve conduction, demyelination and axonal loss. From these results, S100A4 mimetics emerge as a possible means to enhance axonal sprouting and survival, especially in the context of demyelinating neuropathies with secondary axonal loss, such as Charcot-Marie-Tooth type 1 disease. Moreover, our data suggest that S100A4 is a neuroprotectant in PNS and that other S10C proteins, sharing high homology in the H3 motif, may have important functions in PNS pathologies.

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Metastasis-associated Mts1 (S100A4) protein is selectively expressed in white matter astrocytes and is up-regulated after peripheral nerve or dorsal root injury

Cited by 51 publications

References 25 publications

Molecular Mechanisms of Ca²⁺ Signaling in Neurons Induced by the S100A4 Protein

Molecular Mechanisms of Ca²⁺ Signaling in Neurons Induced by the S100A4 Protein

S100A16, a Novel Calcium-binding Protein of the EF-hand Superfamily

Peptide Mimetic of the S100A4 Protein Modulates Peripheral Nerve Regeneration and Attenuates the Progression of Neuropathy in Myelin Protein P0 Null Mice

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Metastasis-associated Mts1 (S100A4) protein is selectively expressed in white matter astrocytes and is up-regulated after peripheral nerve or dorsal root injury

Cited by 51 publications

References 25 publications

Molecular Mechanisms of Ca2+ Signaling in Neurons Induced by the S100A4 Protein

Molecular Mechanisms of Ca2+ Signaling in Neurons Induced by the S100A4 Protein

S100A16, a Novel Calcium-binding Protein of the EF-hand Superfamily

Peptide Mimetic of the S100A4 Protein Modulates Peripheral Nerve Regeneration and Attenuates the Progression of Neuropathy in Myelin Protein P0 Null Mice

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Molecular Mechanisms of Ca²⁺ Signaling in Neurons Induced by the S100A4 Protein

Molecular Mechanisms of Ca²⁺ Signaling in Neurons Induced by the S100A4 Protein