We have found using differential display of
mRNA that the
growth factor heregulin beta 1 (
HRG), a combinatorial
ligand for human
epidermal growth factor receptors (HERs), induced expression of G3BP, the
Ras GTPase-activating
protein SH3 domain-
binding protein, in
breast cancer cells. G3BP is a downstream effector
protein of Ras signaling with
ATP-dependent
RNase and helicase activities, which may link Ras signaling with
RNA turnover and cell cycle progression. In human
breast cancer cells,
HRG induced G3BP
mRNA and
protein expression. Up-regulation of G3BP was found in MCF7
breast cancer cells overexpressing HER2. G3BP was also overexpressed in human
breast tumors in parallel with HER2 overexpression and in an
estrogen-independent manner, suggesting a role for G3BP in
cancer progression. In addition,
HRG stimulation of
breast cancer cells promoted phosphorylation of G3BP and increased the association of G3BP with
GTPase-activating protein, both of which are essential for G3BP activity. G3BP
ATPase activity was also significantly increased by
HRG treatment. Furthermore,
HRG treatment resulted in G3BP translocation to the nucleus and colocalization with acetylated
histone H3, a hallmark of active transcription sites. G3BP induction, phosphorylation,
ATPase activity, and relocalization after
HRG treatment could all be blocked by pretreatment with the anti-receptor HER2
monoclonal antibody Herceptin (
trastuzumab), which may suggest additional applications for this therapeutic antibody. These findings demonstrate for the first time the receptor-dependent regulation of G3BP, a downstream effector of Ras signaling, by
HRG, a
growth factor with diverse functions in
breast cancer cells.