BCR/ABL and IL-3 activate Rap1 to stimulate the B-Raf/MEK/Erk and Akt signaling pathways and to regulate proliferation, apoptosis, and adhesion

Role of SPA-1 in Phenotypes of Chronic Myelogenous Leukemia Induced by BCR-ABL–Expressing Hematopoietic Progenitors in a Mouse Model

“…Second, SPA-1 À/À BCR-ABL + progenitors might show enhanced proliferation and/or survival in vivo. It was reported recently that BCR-ABL-induced Rap1 activation contributed to ERK and Akt activation via B-Raf/MAPK/ERK kinase 1, causing enhanced proliferation and reduced apoptosis in myeloid cells (20). However, ERK activation in present BCR-ABL + cell lines was affected only barely, if any, by SPA-1 overexpression, 5 and possible role of ERK activation remained to be seen.…”

“…The effects of BCR-ABL on cell adhesion have been a matter of argument (38)(39)(40)(41)(42). Recent reports, however, indicated that BCR-ABL enhanced basal cell adhesion in the absence of cytokines, whereas it rather inhibited IL-3-induced cell adhesion (20,43). Present results showed that BCR-ABL enhanced integrin-mediated cell adhesion in both primary HPC and cell lines and that SPA-1 overexpression abolished the enhanced cell adhesion concomitantly with abrogation of Rap1 activation.…”

“…Recent reports also indicated that BCR-ABL induced constitutive Rap1 activation in hematopoietic cells (18,19) and that this in part mediated enhanced proliferation, survival, and cell adhesion (20).…”

Sorafenib Induces Apoptosis Specifically in Cells Expressing BCR/ABL by Inhibiting Its Kinase Activity to Activate the Intrinsic Mitochondrial Pathway

“…BCR/ ABL activates various intracellular signaling pathways, such as those involving Ras, Raf-1, extracellular signal-regulated kinase (Erk), phosphatidylinositol 3-kinase, STAT5, and nuclear factor-nB, which normally play roles in regulation of hematopoiesis by hematopoietic cytokines and other extracellular stimuli (1,2). We have recently shown that BCR/ABL also activates signaling pathways involving Rap1 and B-Raf, which play important roles in induction of cell proliferation and inhibition of apoptosis (9). Thus, inhibitors for the Raf-1 and B-Raf kinases should be attractive candidates for the development of novel therapies against the imatinib resistance.…”

Rottlerin synergistically enhances imatinib-induced apoptosis of BCR/ABL-expressing cells through its mitochondrial uncoupling effect independent of protein kinase C-δ

“…The BCR/ ABL fusion protein is a tyrosine kinase that is constitutively activated and confers survival and proliferation advantages to hematopoietic cells, thus contributing to leukemogenesis. BCR/ABL activates various intracellular signaling pathways, such as those involving Ras, Rap1, B-Raf, Raf-1, Erk, phosphatidylinositol 3-kinase, STAT5 and NFkB, which normally play roles in regulation of hematopoiesis by hematopoietic cytokines and other extracellular stimuli (Goldman and Melo, 2003;Wong and Witte, 2004;Jin et al, 2006). Imatinib (STI-571), a tyrosine kinase inhibitor that blocks the catalytic activity of BCR/ABL, has demonstrated the striking efficacy in treatment of CML or Ph chromosome-positive ALL (Goldman and Melo, 2003;Wong and Witte, 2004;Deininger et al, 2005;O'Hare et al, 2006).…”