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, 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.
Sakaguchi
Masakiyo
M
Department of Cell Biology and Department of Bacteriology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Shikata-chou, Okayama 700-8558, Japan.
Murata
Hitoshi
H
Sonegawa
Hiroyuki
H
Sakaguchi
Yoshihiko
Y
Futami
Jun-ichiro
J
Kitazoe
Midori
M
Yamada
Hidenori
H
Huh
Nam-ho
NH
D017305:Annexin A1 / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism*; D002402:Cathepsin D / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D054510:Phospholipases A2, Cytosolic / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D017305:Annexin A1; D009418:S100 Proteins; D025521:Tumor Suppressor Proteins; C072337:S100A11 protein, human; D004815:Epidermal Growth Factor; D054510:Phospholipases A2, Cytosolic; D002402:Cathepsin D; D002118:Calcium