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Fig. 1 | Cell Communication and Signaling

Fig. 1

From: Role of the ABL tyrosine kinases in the epithelial–mesenchymal transition and the metastatic cascade

Fig. 1

Representation of the ABL structural domains and regulation of ABL kinase activity. a There are 2 major splice variants of ABL1 and ABL2, the 1A isoforms (straight line) and the 1B isoforms (jagged line); numbering uses the 1B isoform. The amino (N)-termini of the ABL kinases contain the SRC homology 3 (SH3), SH2 and SH1 (tyrosine kinase) domains. The carboxyl C-termini of the ABL kinases are divergent with only a conserved filamentous (F)-actin-binding domain (BD) between both paralogs. ABL1 has a globular (G)-actin-binding domain and a DNA-binding domain, whereas ABL2 has a second internal F-actin-binding domain and a microtubule (MT)-binding domain. ABL1 has three nuclear localization signal (NLS) motifs (three green lines located near the SH1 domain) and one nuclear export signal (NES) (single red line in FA BD) in its C terminus. Both paralogs have conserved XPxXP motifs to mediate protein–protein interactions (denoted as black vertical lines in both structures). P131/158L is a mutation that destroys SH3-mediated interactions and R171/198 K is a mutation that destroys SH2-mediated interactions. L290/317R are kinase inactivating mutations. b Inactive and active forms of the ABL kinases are regulated by dynamic intramolecular interactions that modulate ABL kinase activity. The SH3 domain binds to the linker sequence connecting the SH2 and the kinase (SH1) domains, and the SH2 domain interacts with the C-terminal lobe of the kinase domain forming an SH3–SH2 clamp structure locking the kinase in an inactive state. The dashed line represents ABL N-terminal sequences upstream of the SH3 domain that fold over and bind to the myristoyl group in a pocket of the C-lobe of the kinase domain. The myristoylated residue is present in in the N terminus of the ABL 1B isoforms and creates a hydrophobic pocket within the C-lobe of the kinase domain that stabilizes the auto-inhibited conformation. Activation of the ABL kinases by diverse stimuli disrupts the inhibitory intra-molecular interactions. Phosphorylation within the activation loop of (Y412 in ABL1; Y439 in ABL2) as well as within the SH2-kinase domain linker (Y245 in ABL1; Y272 in ABL2) stabilizes the active conformation. Binding of pharmacological inhibitors to the ATP-binding site (Nilotinib or Imatinib) or to the allosteric site (GNF5 or ABL001) disrupts these interactions and causes kinase inhibition by eliciting different conformations

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