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J. Biol. Chem., Vol. 277, Issue 42, 39599-39608, October 18, 2002
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From the Center for Cell Biology & Cancer Research, Albany Medical
College, Albany, New York 12208
Transforming growth factor-
Regulation of HEF1 Expression and Phosphorylation by TGF-
1
and Cell Adhesion*
and
1 (TGF-1)
is a multipotential cytokine, which regulates remodeling of tissue
extracellular matrix during early tumorigenesis and wound healing.
Human enhancer of filamentation-1 (HEF1), a multifunctional
docking protein, is involved in integrin-based signaling, which affects
cell motility, growth, and apoptosis. Our studies reveal that TGF-1
is a potent inducer of HEF1 gene transcription in human
dermal fibroblasts. TGF-1 promoted HEF1 expression in a
dose-dependent manner and resulted in a 16-fold increase in
HEF1 protein level. TGF-1 had no effect on the stability of either
HEF1 protein or mRNA. The TGF-1-induced HEF1 expression was
independent of cell adhesion and resistant to cytoskeleton disruption.
TGF-1 increased levels of both p105 and p115 HEF1 in adherent
fibroblasts. Digestion with specific phosphatases indicated that the
p115HEF1 resulted from serine/threonine phosphorylation of p105HEF1.
The appearance of the p115HEF1 as well as tyrosine phosphorylation of
p105HEF1 required cell adhesion and/or an organized cytoskeleton. An
in vitro kinase assay indicated that p105HEF1 was a
substrate for Src. PP1, a specific Src kinase inhibitor, was able to
block adhesion-dependent tyrosine phosphorylation of
p105HEF1. These findings suggest that TGF-1 regulates
HEF1 gene expression and that HEF1 phosphorylation is
dependent on cell adhesion and Src kinase activity.
*
This work was supported by Grant CA-69612 from the National
Institutes of Health.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence may be addressed. Tel.: 518-262-5698; Fax:
518-262-5696; E-mail: zhengm@mail.amc.edu or
Mckeowp@mail.amc.edu.
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