Whether or not this phos phorylation is functionally considerable remains to become studied. However, the obtaining that SHIP is impacted by Epo therapy raises an interesting possibility, it was lately shown for any assortment of protein phosphatases that they turn into transiently inactivated by reversible oxidation upon recruitment to active receptor complexes. Moderate activation of PI3K in mixture with an inactivation of SHIP could cause a huge raise in signal trans ducing phosphoinositides. Lastly, PI3K not simply displays PI kinase activity but also can function as a protein kinase. At present it is actually not clear whether the protein kinase activity of PI3K plays a function in Epo signaling, by way of example inside the activation of a PKC or Ras.
In summary, our benefits lead us to propose a new model for Epo signaling in which PI3K gives a basal mecha nism to transmit Epo signals to Ras, MEKs and Erks, pos sibly independent in the multiple tyrosines in the cytoplasmic tail with the EpoR. No matter if PI3K is activated through dig this direct or indirect interactions using the EpoR remains to be determined. The basal Epo signal could be modulated and amplified by other signaling pathways activated by greater concen trations of Epo which rely on phosphorylated EpoR tyrosines. If this model is right, a single would anticipate that the absence on the EpoR tyrosines would bring about an impaired response when the erythroid cell compartment is challenged by severe blood loss or hemolysis.
Even though this manuscript was becoming ready, a novel study by Woj chowski and co workers reported precisely this acquiring in mice having a truncated and mutated EpoR devoid of the tyrosine residues that are known to serve as docking sites for several SH2 domain containing Diabex signaling pro teins. Conclusions Erythropoietin can be a essential regulator of erythropoiesis and drives progenitor cell proliferation at the same time as differentia tion. The signaling mechanism by means of which Epo acti vates the mitogenic kinases in key erythroid progenitors was until now largely unclear, in portion mainly because only really couple of in depth biochemical research with primary progenitors happen to be performed so far. Our studies recognize a novel signaling pathway from erythropoietin towards the mitogenic MEK and Erk kinases that needs only minimal amounts of Epo and is as a result believed to reflect the continuous signaling that happens beneath circumstances of blood homeostasis.
Especially, minimal levels of Epo which cause a basal activation from the MEK and Erk kinases moderately activate the class Ib PI3 kinase isoform PI3K. That is, to our knowledge, the first time that the activity of endogenously expressed PI3K has been quan tified. Three distinct PI3K inhibitors, that are structur ally and mechanistically distinct, unexpectedly showed that PI3K activation is crucial for MEK and Erk activa tion.