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Ceramide‐1‐phosphate activates pro‐mitogenic signaling pathways in vascular smooth muscle cells
Author(s) -
Houck Kristy Lee,
Fox Todd,
Kester Mark
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1121
Subject(s) - protein kinase b , mapk/erk pathway , microbiology and biotechnology , ceramide , phosphorylation , signal transduction , pi3k/akt/mtor pathway , chemistry , cell growth , vascular smooth muscle , biology , biochemistry , endocrinology , apoptosis , smooth muscle
Ceramide‐1‐phosphate (C‐1‐P) has been shown to regulate many physiological processes, including cell proliferation, phagocytosis, and inflammation. IL‐1β, an inflammatory agonist, has been shown to induce rapid increases in endogenous C‐1‐P levels (Chalfant et al, J Cell Sci , 2005, 118: 4605) and activates ceramide kinase (CERK) in diverse cell types (Pettus et al, Mol. Pharmacology, 2005, 68: 330). However, there is little known about how CERK is activated in responses to inflammatory or pro‐mitogenic agonists. It is thought that C‐1‐P may inhibit protein phosphatase 1 and 2A to activate the pro‐mitogenic ERK cascade. (Chalfant et al, J Cell Sci , 2005, 118: 4605, Dougherty et al, Mol Cell , 2005, 17:215). In addition, C‐1‐P stimulates ERK2 phosphorylation in osteoblastic cells (Carpio et al, Prostaglandins LeukotEssent Fatty Acids , 1999, 61:267) and stimulates the PI 3 K/Akt pathway leading to cell survival (Gómez‐Muñoz et al, FEBS Letters , 2005, 579:3744). It is thus hypothesized that activation of CERK through a growth factor‐mediated mechanism leads to increased levels of C‐1‐P that can then activate the ERK and Akt pathways in vascular smooth muscles. Our lab has previously shown that increased activation of ERK and Akt occurs after carotid artery balloon angioplasty (Charles et al, Circulation Research , 2000, 87:282). We now show that addition of exogenous C‐1‐P localizes in lipid rafts and leads to activation of Akt. In addition, we demonstrate that PDGF‐activated CERK leads to phosphorylation of ERK in A7r5 vascular smooth muscle cells. Inhibition of CERK‐generated C‐1‐P may be an ideal pharmacological target for the development of anti‐angiogenic or anti‐restenotic therapies. The abstract was funded, in part, by NIH R01 HL66371 to MK.