Metastasis-associated Protein S100A4 Induces Angiogenesis through Interaction with Annexin II and Accelerated Plasmin Formation

Semov, Alexandre; Moreno, María; Onichtchenko, Anatoli; Abulrob, Abedelnasser; Ball, Marguerite; Ekiel, Irena; Pietrzyński, G.; Stanimirovic, Danica; Alakhov, Valery

doi:10.1074/jbc.m412653200

Cited by 210 publications

(207 citation statements)

References 55 publications

(70 reference statements)

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“…To test this hypothesis, a physiologically relevant in vitro branching morphogenesis assay (Fata et al, 2007) was utilized, and indeed, the results demonstrated that S100A4 positively regulated the branching phenotype of primary organoids embedded in Matrigel. In light of the results discussed above, and numerous previous studies where S100A4 induces cell motility, proteolytic activity, and/or invasion in various cell types (Ambartsumian et al, 2001;Saleem et al, 2006;Schmidt-Hansen et al, 2004;Semov et al, 2005;Takenaga and Kozlova, 2006;Tarabykina et al, 2007;Zou et al, 2005), this finding may explain how S100A4 significantly contributes to the aggressiveness of mammary carcinoma cells. The obtained results show that S100A4 induces an invasive and proteolytic phenotype in normal mammary epithelial cells.…”

Section: Discussionsupporting

confidence: 55%

370 The metastasis-promoting protein, S100A4, regulates mammary branching morphogenesis

Andersen¹,

Mori²,

Fata³

et al. 2010

European Journal of Cancer Supplements

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High levels of the S100 calcium binding protein S100A4 also called fibroblast specific protein 1 (FSP1) have been established as an inducer of metastasis and indicator of poor prognosis in breast cancer. The mechanism by which S100A4 leads to increased cancer aggressiveness has yet to be established; moreover, the function of this protein in normal mammary gland biology has not been investigated. To address the role of S100A4 in normal mammary gland, its spatial and temporal expression patterns and possible function in branching morphogenesis were investigated. We show that the protein is expressed mainly in cells of the stromal compartment of adult humans, and during active ductal development, in pregnancy and in involution of mouse mammary gland. In 3D culture models, topical addition of S1004 induced significant increase in the TGFα mediated branching phenotype and a concomitant increase in expression of a previously identified branching morphogen, metalloproteinase-3 (MMP-3). These events were found to be dependent on MEK activation. Downregulation of S100A4 using shRNA significantly reduced TGFα induced branching and altered E-cadherin localization. These findings provide evidence that S100A4 is developmentally regulated and that it plays a functional role in mammary gland development by, in concert with TGFα, activating MMP-3, thereby increasing invasion into the fat pad during branching. We suggest that S100A4-mediated effects during branching morphogenesis provide a plausible mechanism for how it may function in breast cancer progression.

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Section: Discussionsupporting

confidence: 55%

370 The metastasis-promoting protein, S100A4, regulates mammary branching morphogenesis

Andersen¹,

Mori²,

Fata³

et al. 2010

European Journal of Cancer Supplements

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“…Although S100A10 is the best-characterised binding partner, annexin 2 has also been shown to interact with other S100 family members. For example, an interaction with S100A4 has been described (Semov et al, 2005). This interaction was accompanied by accelerated tPA-mediated plasminogen activation in solution as well as on endothelial cell surfaces (Semov et al, 2005), similar to that described for the Anx2/S100A10 complex.…”

Section: Discussionmentioning

confidence: 73%

“…For example, an interaction with S100A4 has been described (Semov et al, 2005). This interaction was accompanied by accelerated tPA-mediated plasminogen activation in solution as well as on endothelial cell surfaces (Semov et al, 2005), similar to that described for the Anx2/S100A10 complex. Interaction with S100A6 has also been reported (Zeng et al, 1993).…”

Section: Discussionmentioning

confidence: 73%

S100A6 binds to annexin 2 in pancreatic cancer cells and promotes pancreatic cancer cell motility

et al. 2009

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BACKGROUND: High levels of S100A6 have been associated with poor outcome in pancreatic cancer patients. The functional role of S100A6 is, however, poorly understood. METHODS: Immunoprecipitation followed by two-dimensional gel electrophoresis and mass spectrometry were undertaken to identify S100A6 interacting proteins in pancreatic cancer cells. Immunohistochemistry and coimmunofluorescence were performed to examine expression or colocalisation of proteins. siRNA was used to deplete specific proteins and effects on motility were measured using Boyden Chamber and wound healing assays. RESULTS: Our proteomic screen to identify S100A6 interacting proteins revealed annexin 11, annexin 2, tropomyosin b and a candidate novel interactor lamin B1. Of these, annexin 2 was considered particularly interesting, as, like S100A6, it is expressed early in the development of pancreatic cancer and overexpression occurs with high frequency in invasive cancer. Reciprocal immunoprecipitation confirmed the interaction between annexin 2 and S100A6 and the proteins colocalised, particularly in the plasma membrane of cultured pancreatic cancer cells and primary pancreatic tumour tissue. Analysis of primary pancreatic cancer specimens (n ¼ 55) revealed a strong association between high levels of cytoplasmic S100A6 and the presence of annexin 2 in the plasma membrane of cancer cells (P ¼ 0.009). Depletion of S100A6 was accompanied by diminished levels of membrane annexin 2 and caused a pronounced reduction in the motility of pancreatic cancer cells. CONCLUSION: These findings point towards a functional role for S100A6 that may help explain the link between S100A6 expression in pancreatic cancer and aggressive disease.

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“…A similar complex is believed to form between the N-terminal domain of AnxA2 and S100A4, although detailed structural data are not available for this heterotetramer. Different from (p11) 2 (AnxA2) 2 , this interaction occurs on the extracellular surface of endothelial cells and accelerates plasmin formation, contributing to tumorinduced angiogenesis (Semov et al, 2005).…”

Section: Introductionmentioning

confidence: 97%

Structure of a C-terminal AHNAK peptide in a 1:2:2 complex with S100A10 and an acetylated N-terminal peptide of annexin A2

Ozorowski

Milton

Luecke

2012

Acta Crystallogr D Biol Cryst

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AHNAK, a large 629 kDa protein, has been implicated in membrane repair, and the annexin A2–S100A10 heterotetramer [(p11)2(AnxA2)2)] has high affinity for several regions of its 1002‐amino‐acid C‐terminal domain. (p11)2(AnxA2)2 is often localized near the plasma membrane, and this C2‐symmetric platform is proposed to be involved in the bridging of membrane vesicles and trafficking of proteins to the plasma membrane. All three proteins co‐localize at the intracellular face of the plasma membrane in a Ca2+‐dependent manner. The binding of AHNAK to (p11)2(AnxA2)2 has been studied previously, and a minimal binding motif has been mapped to a 20‐amino‐acid peptide corresponding to residues 5654–5673 of the AHNAK C‐terminal domain. Here, the 2.5 Å resolution crystal structure of this 20‐amino‐acid peptide of AHNAK bound to the AnxA2–S100A10 heterotetramer (1:2:2 symmetry) is presented, which confirms the asymmetric arrangement first described by Rezvanpour and coworkers and explains why the binding motif has high affinity for (p11)2(AnxA2)2. Binding of AHNAK to the surface of (p11)2(AnxA2)2 is governed by several hydrophobic interactions between side chains of AHNAK and pockets on S100A10. The pockets are large enough to accommodate a variety of hydrophobic side chains, allowing the consensus sequence to be more general. Additionally, the various hydrogen bonds formed between the AHNAK peptide and (p11)2(AnxA2)2 most often involve backbone atoms of AHNAK; as a result, the side chains, particularly those that point away from S100A10/AnxA2 towards the solvent, are largely interchangeable. While the structure‐based consensus sequence allows interactions with various stretches of the AHNAK C‐terminal domain, comparison with other S100 structures reveals that the sequence has been optimized for binding to S100A10. This model adds new insight to the understanding of the specific interactions that occur in this membrane‐repair scaffold.

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Metastasis-associated Protein S100A4 Induces Angiogenesis through Interaction with Annexin II and Accelerated Plasmin Formation

Cited by 210 publications

References 55 publications

370 The metastasis-promoting protein, S100A4, regulates mammary branching morphogenesis

370 The metastasis-promoting protein, S100A4, regulates mammary branching morphogenesis

S100A6 binds to annexin 2 in pancreatic cancer cells and promotes pancreatic cancer cell motility

Structure of a C-terminal AHNAK peptide in a 1:2:2 complex with S100A10 and an acetylated N-terminal peptide of annexin A2

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