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

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, molec...

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Published in:The Journal of biological chemistry 2007-12, Vol.282 (49), p.35679-35686
Main Authors: Sakaguchi, Masakiyo, Murata, Hitoshi, Sonegawa, Hiroyuki, Sakaguchi, Yoshihiko, Futami, Jun-ichiro, Kitazoe, Midori, Yamada, Hidenori, Huh, Nam-ho
Format: Article
Language:English
Subjects:
Annexin A1 - genetics
Annexin A1 - metabolism
Apoptosis - genetics
Calcium - metabolism
Carcinoma, Squamous Cell - genetics
Carcinoma, Squamous Cell - metabolism
Cathepsin D - genetics
Cathepsin D - metabolism
Cell Line, Tumor
Epidermal Growth Factor - genetics
Epidermal Growth Factor - metabolism
Humans
Keratinocytes - metabolism
Phospholipases A2, Cytosolic - genetics
Phospholipases A2, Cytosolic - metabolism
Protein Binding - genetics
S100 Proteins - genetics
S100 Proteins - metabolism
Signal Transduction - genetics
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - metabolism
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Summary: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 A2 (cPLA2), an initiator enzyme of the arachidonic acid cascade, through interaction with S100A11 in normal human keratinocytes (NHK). Ca2+-dependent binding of S100A11 to ANXA1 facilitated the binding of the latter to cPLA2, resulting in inhibition of cPLA2 activity, which is essential for the growth of NHK. On exposure of NHK to epidermal growth factor, ANXA1 was cleaved solely at Trp12, 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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M707538200