To determine how AKT2 might contribute to
tumor cell progression, a full-length, wild-type,
human AKT2/protein kinase B (PKB)beta
cDNA was transfected into a panel of eight human breast and
ovarian cancer cells. AKT2 transfectants demonstrated increased adhesion and invasion through
collagen IV because of up-regulation of beta1
integrins. In addition, AKT2 cells were more metastatic than control cells in vivo. Increased invasion by AKT2 was blocked by preincubation with an anti-beta1
integrin function blocking antibody, exposure to
wortmannin, and by expression of
phosphatase and
tensin homologue
tumor suppressor (PTEN). Confocal microscopy performed on transfected human
breast cancer cells showed that unlike AKT1, AKT2
protein predominantly localized adjacent to the
collagen IV matrix during cellular attachment. Overexpression of AKT2, but not AKT1 or AKT3, was sufficient to duplicate the invasive effects of
phosphoinositide 3-OH
kinase (PI3-K) transfected in
breast cancer cells. Furthermore, expression of
kinase dead AKT2(181
amino acid methionine [M]), and not
kinase dead AKT1(179M) or AKT3(177M), was capable of blocking invasion induced by either human
epidermal growth factor receptor-2 (HER-2) overexpression or by activation of PI3-K. Taken together, these data indicate that AKT2 mediates PI3-K-dependent effects on adhesion, motility, invasion, and
metastasis in vivo.