PKCα mediates TGFβ-induced growth inhibition of human keratinocytes via phosphorylation of S100C/A11

Abstract

Growth regulation of epithelial cells is of major concern because most human cancers arise from them. We demonstrated previously a novel signal pathway involving S100C/A11 for high Ca2+-induced growth inhibition of normal human keratinocytes (Sakaguchi, M., M. Miyazaki, M. Takaishi, Y. Sakaguchi, E. Makino, N. Kataoka, H. Yamada, M. Namba, and N.H. Huh. 2003. J. Cell Biol. 163:825–835). This paper addresses a question whether transforming growth factor β (TGFβ) shares the pathway with high Ca2+. On exposure of the cells to TGFβ1, S100C/A11 was phosphorylated, bound to nucleolin, and transferred to the nucleus, resulting in induction of p21WAF1/CIP1 and p15INK4B through activation of Sp1. Protein kinase C α (PKCα) was shown to phosphorylate 10Thr of S100C/A11, which is a critical event for the signal transduction. The TGFβ1-induced growth inhibition was almost completely mitigated when PKCα activity was blocked or when S100C/A11 was functionally sequestered. These results indicate that, in addition to the well-characterized Smad-mediated pathway, the PKCα–S100C/A11-mediated pathway is involved in and essential for the growth inhibition of normal human keratinocytes cells by TGFβ1.

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

“…Thr 10 and Ser 94 (18), showed a binding mode similar to that of the wild-type protein. Endogenous S100A11 and cPLA 2 were pulled down by GST-ANXA1 added to the cell extracts (supplemental Fig.…”

“…4A). We previously showed that S100A11 functions as an essential mediator for growth suppression of NHK by high Ca 2ϩ and TGF␤ (18,19,21). S100A11 is phosphorylated by protein kinase C␣ as a prerequisite for translocation into the nucleus and induction of p21 WAF1 .…”

“…Although a model for membrane rearrangement by the ANXA1-S100A11 complex has been proposed (1), the biological relevance and action mechanism of the complex formation remain to be clarified. We recently demonstrated that S100A11 is involved in TGF␤-triggered signaling (18,19). On exposure of normal human keratinocytes (NHK) to TGF␤, S100A11 was phosphorylated by protein kinase C␣ and transferred to the nucleus, resulting in induction of p21 WAF1 .…”

Defective IgG2a/2b Class Switching in PKCα−/− Mice

“…Selective knockdown studies of PKC␣ (via antisense oligonucleotides, RNA interference as well as pharmacological inhibitors), and biochemical studies using PKC isotypespecific cDNA (wt, constitutively active, and dominant negative), already strongly implicated a role of PKC␣ in the control of cell cycle machinery. Importantly, the biological responses obtained by the manipulation of PKC␣ were found to be cell-type specific (17); it promoted proliferation in some types of cells (human breast cancer cells, neonatal cardiomyocytes (22), and mediated cell cycle arrest in other cell types (epithelial cells) by inducing cyclindependent kinase inhibitors, p21 Waf1/Cip1 (23) and p27 Kip1 (24). The distinct responses are modulated by dynamic interactions with cell-type-specific anchoring proteins such as the receptor for activated PKC, vinculin, talin, ␤ 1 integrin, and caveolin.…”

MALDI-MSI and Ovarian Cancer Biomarkers

“…S100 A11 has been detected in ovarian ascites 73 . S100 A11 (or calgizzarin) is known to regulate cell growth by inhibiting DNA synthesis 86,87 . S100 A12 is known to contribute to leukocyte migration in chronic inflammatory responses 88 .…”