Figure 1
Figure 1. BCR-ABL signaling mimics growth factor activation. Growth factors are known to activate receptor tyrosine kinases (RTKs), leading to the activation of the RAS and PI3K/AKT pathways. These pathways are commonly activated in human cancers. Phosphorylation of tyrosine 177 within the BCR part of BCR-ABL leads similarly to activation of these pathways by interacting with the SH2 domain in GRB2. GRB2 activates RAS by interacting with Son of Sevenless (SOS), and it also activates PI3K by mediating phosphorylation of GAB2. Constitutive activation of PI3K leads to conversion of phosphatidylinositol bisphosphate (PIP2) to phosphatidylinositol triphosphate (PIP3). This can be inhibited by phosphatase and tensin homolog (PTEN), a phosphatase that is down-regulated in many cancers. PIP3 provides a platform for the recruitment of the serine/threonine kinases AKT and 3-phosphoinositide-dependent protein kinase-1 (PDK1), leading to phosphorylation and activation of AKT. Activated AKT phosphorylates many downstream targets that affect proliferation and survival, including the FOXO transcription factors and the proapoptotic protein BAD. AKT-mediated phosphorylation of FOXO inhibits its nuclear entry and therefore suppresses its activity, leading to increased cell proliferation. The proapoptotic activity of BAD is also suppressed after AKT-mediated phosphorylation. Phosphorylation of BAD prevents it binding to and inhibiting the function of antiapoptotic BCL-2 proteins that inhibit the proapoptotic proteins BAK and BAX. AKT activation leads to down-regulation of the tumor suppressor p53 by increasing the levels of the negative regulator of p53, MDM2. AKT also phosphorylates the serine/threonine kinase mTOR. Activated mTOR promotes protein translation and inhibits autophagy. BCR-ABL also leads to the activation of the JAK/STAT pathway, a pathway that is frequently activated in myeloproliferative diseases. JAK is a nonreceptor tyrosine kinase and is normally activated by growth factors. BCR-ABL has been shown to induce IL-3 and G-CSF production that could lead to activation of this pathway. Active JAK phosphorylates the transcription factor STAT5 and BCR-ABL has also been shown to directly phosphorylate STAT5, leading to increased proliferation.

BCR-ABL signaling mimics growth factor activation. Growth factors are known to activate receptor tyrosine kinases (RTKs), leading to the activation of the RAS and PI3K/AKT pathways. These pathways are commonly activated in human cancers. Phosphorylation of tyrosine 177 within the BCR part of BCR-ABL leads similarly to activation of these pathways by interacting with the SH2 domain in GRB2. GRB2 activates RAS by interacting with Son of Sevenless (SOS), and it also activates PI3K by mediating phosphorylation of GAB2. Constitutive activation of PI3K leads to conversion of phosphatidylinositol bisphosphate (PIP2) to phosphatidylinositol triphosphate (PIP3). This can be inhibited by phosphatase and tensin homolog (PTEN), a phosphatase that is down-regulated in many cancers. PIP3 provides a platform for the recruitment of the serine/threonine kinases AKT and 3-phosphoinositide-dependent protein kinase-1 (PDK1), leading to phosphorylation and activation of AKT. Activated AKT phosphorylates many downstream targets that affect proliferation and survival, including the FOXO transcription factors and the proapoptotic protein BAD. AKT-mediated phosphorylation of FOXO inhibits its nuclear entry and therefore suppresses its activity, leading to increased cell proliferation. The proapoptotic activity of BAD is also suppressed after AKT-mediated phosphorylation. Phosphorylation of BAD prevents it binding to and inhibiting the function of antiapoptotic BCL-2 proteins that inhibit the proapoptotic proteins BAK and BAX. AKT activation leads to down-regulation of the tumor suppressor p53 by increasing the levels of the negative regulator of p53, MDM2. AKT also phosphorylates the serine/threonine kinase mTOR. Activated mTOR promotes protein translation and inhibits autophagy. BCR-ABL also leads to the activation of the JAK/STAT pathway, a pathway that is frequently activated in myeloproliferative diseases. JAK is a nonreceptor tyrosine kinase and is normally activated by growth factors. BCR-ABL has been shown to induce IL-3 and G-CSF production that could lead to activation of this pathway. Active JAK phosphorylates the transcription factor STAT5 and BCR-ABL has also been shown to directly phosphorylate STAT5, leading to increased proliferation.

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