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Pref‐1 Activates The MEK/ERK Pathway To Inhibit Adipocyte Differentiation
Author(s) -
wang yuhui,
kim kyungah,
kim junghyun,
sul heisook
Publication year - 2008
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.22.1_supplement.645.5
Subject(s) - mapk/erk pathway , phosphorylation , adipogenesis , adipocyte , microbiology and biotechnology , chemistry , mek inhibitor , gene knockdown , biology , in vitro , biochemistry , adipose tissue , gene
Pref‐1, an EGF‐repeat containing protein, is found in preadipocytes but absent in adipocytes. Pref‐1 is made as a transmembrane protein but is cleaved to generate a biologically active soluble form. Although Pref‐1 inhibition of adipognesis has been well studied in vitro and in vivo, the signaling pathway for Pref‐1 is not known. By using purified soluble Pref‐1 in mouse embryo fibroblasts (MEF), we investigated the mechanism of Pref‐1 in the inhibition of adipocyte differentiation. Pref‐1 increases MEK/ERK phosphorylation in a time‐ and dose‐dependent manner. Compared to wild‐type MEF, differentiation of Pref‐1 null MEF into adipocytes is enhanced. During adipocyte differentiation, both wild‐type and Pref‐1 null MEF show a transient burst of ERK phosphorylation upon addition of adipogenic agents. However, wild‐type MEF show a significant, albeit lower, second increase in ERK phosphorylation peaking at day 2. This ERK phosphorylation, corresponding to Pref‐1 level, is absent during differentiation of Pref‐1 null MEF. Prevention of this second increase in ERK phosphorylation by the MEK inhibitor PD98059 or by knockdown of ERK via siRNA enhances adipocyte differentiation. Conversely, treatment of Pref‐1 null MEF with Pref‐1 restores this ERK phosphorylation, resulting in inhibition of adipocyte differentiation. Our data indicate that Pref‐1 activation of MEK/ERK signaling is required for Pref‐1 inhibition of adipogenesis.