Oligomeric Forms of the Metastasis-related Mts1 (S100A4) Protein Stimulate Neuronal Differentiation in Cultures of Rat Hippocampal Neurons

IT University of Copenhagen, København, Capital Region, Denmark
Journal of Biological Chemistry (Impact Factor: 4.57). 01/2001; 275(52):41278-86. DOI: 10.1074/jbc.M007058200
Source: PubMed


Neuronal differentiation and axonal growth are controlled by a variety of factors including neurotrophic factors, extracellular matrix components, and cell adhesion molecules. Here we describe a novel and very efficient neuritogenic factor, the metastasis-related Mts1 protein, belonging to the S100 protein family. The oligomeric but not the dimeric form of Mts1 strongly induces differentiation of cultured hippocampal neurons. A mutant with a single Y75F amino acid substitution, which stabilizes the dimeric form of Mts1, is unable to promote neurite extension. Disulfide bonds do not play an essential role in the Mts1 neuritogenic activity. Mts1-stimulated neurite outgrowth involves activation of phospholipase C and protein kinase C, depends on the intracellular level of Ca(2+), and requires activation of the extracellular signal-regulated kinases (ERKs) 1 and 2.

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    • "One of the mechanisms for their varied cellular functions is the ability of the majority of S100 proteins to interact directly with a number of other cellular proteins, thereby modulating their functions [3]. Several members of S100 proteins can form homodimers/oligomers (for example: S100A4 [5], S100B [6]) or heterodimers (for example: interactions between S100A8 and S100A9 [7], between S100A4 and S100A1 [8], between S100B and S100A6 [6]) and these homo/heterodimer- formation is considered to be important for their cellular functions. "
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    ABSTRACT: Both S100A14 and S100A16 are members of the multifunctional S100 protein family. Formation of homo/heterodimers is considered to be one of the major mechanisms for S100 proteins to execute their diverse cellular functions. By employing a classical Yeast two hybrid (Y-2 H) screen, we identified S100A16 as the single interaction partner of S100A14. This interaction was verified by co-immunoprecipitation, double indirect immunofluorescence and double immunostaining in specimens of oral squamous cell carcinoma and normal oral mucosa. The functional significance of this interaction was examined by employing retroviral mediated over-expression and knock-down of these proteins in several cancer cell-lines. Over-expression and knock-down of S100A14 led to concomitant up- and down-regulation of S100A16 protein in the cell-lines examined. However, there was no up-regulation of S100A16 mRNA upon S100A14 over-expression, indicating that modulation of S100A16 expression was not due to enhanced transcriptional activity but possibly by post-transcriptional regulation. In contrary, over-expression of S100A16 was associated neither with the up-regulation of S100A14 mRNA nor its protein, suggesting a unidirectional regulation between S100A14 and S100A16. Cellular treatment with protein synthesis inhibitor cycloheximide demonstrated a time-dependent intracellular degradation of both S100A16 and S100A14 proteins. Additionally, regulation of S100A16 and S100A14 degradation was found to be independent of the classical proteasomal and lysosomal pathways of protein degradation. Further studies will therefore be necessary to understand the functional significance of this interaction and the mechanisms on how S100A14 is involved in the regulation of S100A16 expression.
    Full-text · Article · Sep 2013 · PLoS ONE
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    • "Most members of the S100 protein family, except for the monomeric S100G, form a non-covalently associated anti-parallel dimer organized into an eight helix bundle, even in the absence of Ca 2+ . However, several S100 proteins have been reported to assemble into a variety of biologically active multimeric forms larger than a dimer2345. The assembly of the S100A3 tetramer[6], S100A8/S100A9 heterotetramers[4,7,8]and S100A12 hexamer[9]strictly depends on Ca 2+ , while the S100B tetramer is stable in the absence of Ca 2+[5]. "
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    ABSTRACT: The S100A3 homotetramer assembles upon citrullination of a specific symmetric Arg51 pair on its homodimer interface in human hair cuticular cells. Each S100A3 subunit contains two EF-hand-type Ca2 +-binding motifs and one (Cys)3His-type Zn2 +-binding site in the C-terminus. The C-terminal coiled domain is cross-linked to the presumed docking surface of the dimeric S100A3 via a disulfide bridge. The aim of this study was to determine the structural and functional role of the C-terminal Zn2 +-binding domain, which is unique to S100A3, in homotetramer assembly. The binding of either Ca2 + or Zn2 + reduced the α-helix content of S100A3 and modulated its affinity for the other cation. The binding of a single Zn2 + accelerated the Ca2 +-dependent tetramerization of S100A3 while inducing an extensive unfolding of helix IV. The Ca2 + and Zn2 + binding affinities of S100A3 were enhanced when the other cation bound in concert with the tetramerization of S100A3. Small angle scattering analyses revealed that the overall structure of the S100A3 tetramer bound both Ca2 + and Zn2 + had a similar molecular shape to the Ca2 +-bound form in solution. The binding states of the Ca2 + or Zn2 + to each S100A3 subunit within a homotetramer appear to be propagated by sensing the repositioning of helix III and the rearrangement of the C-terminal tail domain. This article is part of a Special Issue entitled: 12th European Symposium on Calcium.
    Full-text · Article · Jul 2013 · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
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    • "There is increasing evidence that S100 proteins are able to form higher-order oligomers [14,103–105], though the functional relevance of these complexes is not yet clear. Recently we have found that S100A8/A9 can self-assemble into a variety of amyloid complexes both in vivo and in the test tube in vitro. "
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    ABSTRACT: S100A8 and S100A9 are EF-hand Ca(2+) binding proteins belonging to the S100 family. They are abundant in cytosol of phagocytes and play critical roles in numerous cellular processes such as motility and danger signaling by interacting and modulating the activity of target proteins. S100A8 and S100A9 expression levels increased in many types of cancer, neurodegenerative disorders, inflammatory and autoimmune diseases and they are implicated in the numerous disease pathologies. The Ca(2+) and Zn(2+)-binding properties of S100A8/A9 have a pivotal influence on their conformation and oligomerization state, including self-assembly into homo- and heterodimers, tetramers and larger oligomers. Here we review how the unique chemical and conformational properties of individual proteins and their structural plasticity at the quaternary level account for S100A8/A9 functional diversity. Additional functional diversification occurs via non-covalent assembly into oligomeric and fibrillar amyloid complexes discovered in the aging prostate and reproduced in vitro. This process is also regulated by Ca(2+)and Zn(2+)-binding and effectively competes with the formation of the native complexes. High intrinsic amyloid-forming capacity of S100A8/A9 proteins may lead to their amyloid depositions in numerous ailments characterized by their elevated expression patterns and have additional pathological significance requiring further thorough investigation.
    Full-text · Article · Dec 2012 · International Journal of Molecular Sciences
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