Differential signaling of Flt3 activating mutations in acute myeloid leukemia:a working model

Receptor tyrosine kinases couple a wide variety of extracellular cues to cellular responses.The class III subfamily comprises the platelet-derived growth factor receptor,c-Kit,Flt3 and c-Fms,all of which relay cell proliferation signals upon ligand binding.Accordingly,mutations in these proteins that confer ligand-independent activation are found in a subset of cancers.These mutations cluster in the juxtamembrane(JM)and catalytic tyrosine kinase domain(TKD)regions.In the case of acute myeloid leukemia(AML),the juxtamembrane(named ITD for internal tandem duplication)and TKD Flt3 mutants differ in their spectra of clinical outcomes.Although the mechanism of aberrant activation has been largely elucidated by biochemical and structural analyses of mutant kinases,the differences in disease presentation cannot be attributed to a change in substrate specificity or signaling strength of the catalytic domain.This review discusses the latest literature and presents a working model of differential Flt3 signaling based on mis-localized juxtamembrane autophosphorylation,to account for the disease variation.This will have bearing on therapeutic approaches in a complex disease such as AML,for which no efficacious drug yet exists.

A SPX domain vacuolar transporter links phosphate sensing to homeostasis in Arabidopsis

Excess phosphate(Pi)is stored into the vacuole through Pi transporters so that cytoplasmic Pi levels remain stable in plant cells.We hypothesized that the vacuolar Pi transporters may harbor a Pi-sensing mechanism so that they are activated to deliver Pi into the vacuole only when cytosolic Pi reaches a threshold high level.We tested this hypothesis using Vacuolar Phosphate Transporter 1(VPT1),a SPX domain-containing vacuolar Pi transporter,as a model.Recent studies have defined SPX as a Pi-sensing module that binds inositol polyphosphate signaling molecules(InsPs)produced at high cellular Pi status.We showed here that Pi-deficient conditions or mutation of the SPX domain severely impaired the transport activity of VPT1.We further identified an auto-inhibitory domain in VPT1 that suppresses its transport activity.Taking together the results from detailed structure-function analyses,our study suggests that VPT1 is in the auto-inhibitory state when Pi status is low,whereas at high cellular Pi status InsPs are produced and bind SPX domain to switch on VPT1 activity to deliver Pi into the vacuole.This thus provides an auto-regulatory mechanism for VPT1-mediated Pi sensing and homeostasis in plant cells.