Signaling on location
The most frequent kinase mutation in acute myeloid leukemia is an internal tandem duplication in the RTK Flt3 that causes a prolonged residence of the receptor in cellular compartments such as the ER. This mutant, Flt3-ITD, but not the ligand-activated wild-type receptor, is constitutively active both at the cell surface and intracellularly, phosphorylates STAT5 and upregulates STAT5 targets including the Pim-1/2 kinases. To test whether premature activation of Flt3-ITD at intracellular locations leads to aberrant signaling activation, Choudhary et al. used chemical inhibitors to trap the mutant receptor at defined intracellular locations by modifying receptor glycosylation or adding a myristate moiety to deliver it inappropriately to the plasma membrane. In multiple cell lines, they found that the phosphorylation pattern of Flt3-ITD itself was compartment-specific and the ER-retained form could activate signaling pathways that are different from those activated by the cell surface–localized form. For instance, the authors confirmed by proteomic analysis that Flt3-ITD only signaled to STAT5a/b from the ER. Additionally, phosphorylation sites that fit the Pim-1/2 consensus site had compartment-specific profiles, and there was location-dependent increased tyrosine phosphorylation of several adaptor proteins. Together, these results lend strong support to the concept of signaling compartmentalization and an increased understanding of aberrant signaling by oncogenic RTKs. (Mol. Cell 36, 326–339, 2009) MB
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