Requirement of caspase-mediated cleavage of c-Abl during stress-induced apoptosis

Abstract

c-Abl protein tyrosine kinase plays an important role in cell cycle control and apoptosis. Furthermore, induction of apoptosis correlates with the activation of c-Abl. Here, we demonstrate the cleavage of c-Abl by caspases during apoptosis. Caspases separate c-Abl into functional domains including a Src-kinase, a fragment containing nuclear import sequences, a fragment with an actin-binding domain and nuclear export sequence. Caspase cleavage increases the kinase activity of c-Abl as demonstrated by in vitro kinase assays as well as by auto-and substrate phosphorylation. Cells in which c-Abl expression was knocked down by RNA interference resisted cisplatin-but not TNFa-induced apoptosis. A similar selective resistance against cisplatin-induced apoptosis was observed when cleavage resistant c-Abl was overexpressed in treated cells. Our data suggest the selective requirement of c-Abl cleavage by caspases for stressinduced, but not for TNFa-induced apoptosis.

The tyrosine kinase c‐Abl promotes proliferation and is expressed in atypical teratoid and malignant rhabdoid tumors

“…Here, Western blot analysis revealed a 90-kDa fragment. As unprocessed c-Abl is an approximately 120-kDa protein, this smaller fragment may be explained by cleavage of the protein as demonstrated previously by Machuy et al 29 The finding that ABL1 knockdown resulted in reduced proliferation in both cell lines indicates a functional involvement of c-Abl in the cellular growth of rhabdoid tumor cells in vitro and is well in line with previous findings in extracranial solid tumors, such as breast cancer. [34][35][36] To further evaluate this involvement, we studied blockage of c-Abl signaling by the tyrosine kinase inhibitor imatinib and observed a growth-inhibitory effect against A204 cells and G401 cells that was comparable to the effect observed in breast cancer cell lines that contained highly active c-Abl kinases.…”

“…2C,D), corresponding to the previously described size of truncated c-Abl in cell cultures. 28,29 In addition, A204 cells had membranous PDGFRA expression, whereas PDGFRB and c-Kit staining were lacking. In contrast, G401 cells had membranous PDGFRB expression, but PDGFRA and c-Kit were not expressed.…”

F-actin-binding domain of c-Abl regulates localized phosphorylation of C3G: role of C3G in c-Abl-mediated cell death

“…A Mitra and V Radha (Machuy et al, 2004), but we show for the first time its localized activation to phosphorylate CrkII as well as a novel substrate, C3G. Some of the mechanisms involved in detachment of apoptotic cells are common to those controlling tail retraction during polarized migration.…”

Phosphorylation of Helicobacter pylori CagA by c-Abl leads to cell motility

“…The EPIYA motif analyses of the H. pylori strains P1, P12 and Hp26695 are shown in Figure 4a. All tested CagA proteins possessed the EPIYA-A, EPIYA-B and one EPIYA-C motif, whereas two EPIYA-C motifs were only apparent in the P12 strain (Figure 4a (Barila et al, 2003;Machuy et al, 2004). Instead, our data reveal that the total amount of c-Abl is increased in response to H. pylori infection (Figure 5c, second panel), which might account for target phosphorylation.…”