The tyrosine kinase Abl is required for Src-transforming activity in mouse fibroblasts and human breast cancer cells

Abstract

The cytoplasmic tyrosine kinase Src has been implicated in signal transduction induced by growth factors and integrins. Src also shows oncogenic activity when deregulated. Accumulating evidence indicates that the tyrosine kinase Abl is an important substrate for Src signalling in normal cells. Here we show that Abl is also required for Src-induced transformation of mouse fibroblasts. Abl does not mediate tyrosine phosphorylation of Stat3 and Shc, two important regulators of Src oncogenic activity. In contrast, Abl controls the activation of the small GTPase Rac for oncogenic signalling and active Rac partly rescued Src transformation in cells with inactive Abl. Moreover, Abl mediates Src-induced extracellular regulated kinase 5 (ERK5) activation to drive cell transformation. Finally, we find that Abl/Rac and Abl/ERK5 pathways also operate in human MCF7 and BT549 breast cancer cells, where neoplastic transformation depends on Src-like activities. Therefore, Abl is an important regulator of Src oncogenic activity both in mouse fibroblasts and in human cancer cells. Targeting these Abl-dependent signalling cascades may be of therapeutic value in breast cancers where Src-like function is important.

Src family tyrosine kinases-driven colon cancer cell invasion is induced by Csk membrane delocalization

“…We first confirmed that the Csk substrates SFK have important roles in transforming properties of CRC cells; specifically, anchorage-independent growth and invasion were inhibited by treatment with the SFK pharmacological inhibitor, SU6656 ( Figure 2a). Similar results were obtained in MCF7 and ZR75.1 ER þ breast cancer cells (Figure 2a), which is in agreement with an important role for SFK in ER oncogenic signalling (Ishizawar et al, 2004;Sirvent et al, 2007). In contrast, the SFK inhibitor had no effect on HER2 þ breast cancer cells, SKBR3 and BT474, indicating that SFK do not have a role in every breast cancer cell ( (Sirvent et al, 2007) and not shown).…”

“…Similar results were obtained in MCF7 and ZR75.1 ER þ breast cancer cells (Figure 2a), which is in agreement with an important role for SFK in ER oncogenic signalling (Ishizawar et al, 2004;Sirvent et al, 2007). In contrast, the SFK inhibitor had no effect on HER2 þ breast cancer cells, SKBR3 and BT474, indicating that SFK do not have a role in every breast cancer cell ( (Sirvent et al, 2007) and not shown). Owing to the important function of SFK in CRC cells, we next investigated the role of Csk in the growth and invasion of CRC cells.…”

“…Cell lines (ATCC, Rockville, MD) were cultured, as described previously (Sirvent et al, 2007), in specific growth medium (Invitrogen) supplemented with 10% fetal calf serum: RPMI for SW620, SW480, HCT116, HT29, Colo205 and MCF7; Dulbecco's modified Eagle's media-F-12 for MDAMB231, MDAMB468, ZR75.1 and SKBR3. For drug treatments, cells were treated with the indicated inhibitor (or dimethyl sulfoxide as a vehicle) for 24 h, as indicated, in growth medium supplemented with 1% fetal calf serum.…”

“…For drug treatments, cells were treated with the indicated inhibitor (or dimethyl sulfoxide as a vehicle) for 24 h, as indicated, in growth medium supplemented with 1% fetal calf serum. Retroviral infections were performed as in Sirvent et al (2007) and stable cell lines have been obtained in a polyclonal background by puromycin (1 mg/ml) selection.…”

Activated c-Abl tyrosine kinase in malignant solid tumors

“…Abl as a downstream target of Src in breast cancer is supported by a recent study that shows that a decrease of Src kinase by a known Src inhibitor leads to a decrease of Abl kinase human breast cancer cell lines (Sirvent et al, 2007). Sirvent et al (2007) further show that Abl is involved in a Src/Abl/Rac/JNK/STAT3 signaling cascade that is important in cell transformation.…”