Bifurcated converging pathways for high Ca 2 +- and TGFβ-induced inhibition of growth of normal human keratinocytes

Journal of Biological Chemistry

Murata

Sonegawa

et al. 2007

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Regulation of cell growth and apoptosis is one of the pleiotropic functions of annexin A1 (ANXA1). Although previous reports on the overexpression of ANXA1 in many human cancers and on growth suppression and/or induction of apoptosis by ANXA1 may indicate the tumor-suppressive nature of ANXA1, molecular mechanisms of the function of ANXA1 remain largely unknown. Here we provide evidence that ANXA1 mechanistically links the epidermal growth factor-triggered growth signal pathway with cytosolic phospholipase A 2 (cPLA 2 ), an initiator enzyme of the arachidonic acid cascade, through interaction with S100A11 in normal human keratinocytes (NHK). Ca 2؉ -dependent binding of S100A11 to ANXA1 facilitated the binding of the latter to cPLA 2 , resulting in inhibition of cPLA 2 activity, which is essential for the growth of NHK. On exposure of NHK to epidermal growth factor, ANXA1 was cleaved solely at Trp 12 , and this cleavage was executed by cathepsin D. In squamous cancer cells, this pathway was shown to be constitutively activated. The newly found mechanistic intersection may be a promising target for establishing new measures against human cancer and other cell growth disorders.

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Truncation of Annexin A1 Is a Regulatory Lever for Linking Epidermal Growth Factor Signaling with Cytosolic Phospholipase A2 in Normal and Malignant Squamous Epithelial Cells

Journal of Biological Chemistry

Murata

Sonegawa

et al. 2007

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“…S100A11 (S100C) was cloned from the chicken gizzard in 1991 (Todoroki et al, 1991), and it was later shown to bind to annexin A1 (Mailliard et al, 1996), but its function has remained largely unknown. Because S100A11 is encoded in epidermal differentiation complex on chromosome 1 in humans, we studied the biological role of S100A11 in normal human keratinocytes (NHK), and we found that it is an essential element in the signal transduction for high Ca ϩϩ -and transforming growth factor (TGF)␤-induced suppression of the growth of NHK (Sakaguchi et al, 2003(Sakaguchi et al, , 2005. On exposure of NHK to either agent, S100A11 was transferred to nuclei, where it induces p21 WAF1 .…”

Section: Introductionmentioning

confidence: 99%

“…Blocking the S100A11-mediated pathway abrogated the growth suppression by high Ca ϩϩ and TGF␤, even though the canonical nuclear factor of activated T cells (NFAT)1-mediated pathway for high Ca ϩϩ and the Smad-mediated pathway for TGF␤ remained intact. Thus, high Ca ϩϩ and TGF␤ have a common S100A11-mediated pathway in addition to unique pathways for exhibiting an inhibitory effect on the growth of NHK, and both pathways are indispensable (Sakaguchi et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

S100A11, an Dual Mediator for Growth Regulation of Human Keratinocytes

Sonegawa

Murata

et al. 2008

MBoC

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We previously revealed a novel signal pathway involving S100A11 for inhibition of the growth of normal human keratinocytes (NHK) caused by high Ca ؉؉ or transforming growth factor ␤. Exposure to either agent resulted in transfer of S100A11 to nuclei, where it induced p21 WAF1 . In contrast, S100A11 has been shown to be overexpressed in many human cancers. To address this apparent discrepancy, we analyzed possible new functions of S100A11, and we provide herein evidence that 1) S100A11 is actively secreted by NHK; 2) extracellular S100A11 acts on NHK to enhance the production of epidermal growth factor family proteins, resulting in growth stimulation; 3) receptor for advanced glycation end products, nuclear factor-B, Akt, and cAMP response element-binding protein are involved in the S100A11-triggered signal transduction; and 4) production and secretion of S100A11 are markedly enhanced in human squamous cancer cells. These findings indicate that S100A11 plays a dual role in growth regulation of epithelial cells.

The structure of S100A11 fragment explains a local structural change induced by phosphorylation

Kouno

Mizuguchi

Journal of Peptide Science

et al. 2008

S100A11 protein is a member of the S100 family containing two EF-hand motifs. It undergoes phosphorylation on residue T10 after cell stimulation such as an increase in Ca(2+) concentration. Phosphorylated S100A11 can be recognized by its target protein, nucleolin. Although S100A11 is initially expressed in the cytoplasm, it is transported to the nucleus by the action of nucleolin. In the nucleus, S100A11 suppresses the growth of keratinocytes through p21(CIP1/WAF1) activation and induces cell differentiation. Interestingly, the N-terminal fragment of S100A11 has the same activity as the full-length protein; i.e. it is phosphorylated in vivo and binds to nucleolin. In addition, this fragment leads to the arrest of cultured keratinocyte growth. We examined the solution structure of this fragment peptide and explored its structural properties before and after phosphorylation. In a trifluoroethanol solution, the peptide adopts the alpha-helical structure just as the corresponding region of the full-length S100A11. Phosphorylation induces a disruption of the N-capping conformation of the alpha-helix, and has a tendency to perturb its surrounding structure. Therefore, the phosphorylated threonine lies in the N-terminal edge of the alpha-helix. This local structural change can reasonably explain why the phosphorylation of a residue that is initially buried in the interior of protein allows it to be recognized by the binding partner.