PKC-epsilon deficiency alters progenitor cell populations in favor of megakaryopoiesis

Abstract

BackgroundIt has long been postulated that Protein Kinase C (PKC) is an important regulator of megakaryopoiesis. Recent contributions to the literature have outlined the functions of several individual PKC isoforms with regard to megakaryocyte differentiation and platelet production. However, the exact role of PKCε remains elusive.ObjectiveTo delineate the role of PKCε in megakaryopoiesis.Approach and resultsWe used a PKCε knockout mouse model to examine the effect of PKCε deficiency on platelet mass, megakaryocyte mass, and bone marrow progenitor cell distribution. We also investigated platelet recovery in PKCε null mice and TPO-mediated signaling in PKCε null megakaryocytes. PKCε null mice have higher platelet counts due to increased platelet production compared to WT littermate controls (p<0.05, n = 8). Furthermore, PKCε null mice have more bone marrow megakaryocyte progenitor cells than WT littermate control mice. Additionally, thrombopoietin-mediated signaling is perturbed in PKCε null mice as Akt and ERK1/2 phosphorylation are enhanced in PKCε null megakaryocytes stimulated with thrombopoietin. Finally, in response to immune-induced thrombocytopenia, PKCε null mice recovered faster and had higher rebound thrombocytosis than WT littermate control mice.ConclusionsEnhanced platelet recovery could be due to an increase in megakaryocyte progenitor cells found in PKCε null mice as well as enhanced thrombopoietin-mediated signaling observed in PKCε deficient megakaryocytes. These data suggest that PKCε is a negative regulator of megakaryopoiesis.

Phosphorylation on Syk Y342 is important for both ITAM and hemITAM signaling in platelets

“…We previously showed that several tyrosine residues on Syk are phosphorylated in response to the GPVI agonist convulxin ( 8 , 31 ). Furthermore, we and others have demonstrated that both Syk Y519/520 and Y346 are phosphorylated downstream of CLEC-2 ( 32 , 33 ). Syk Y519/520 is located in the activation loop of Syk and appears to be crucial for Syk signaling ( 34 , 35 , 36 ).…”

micro-RNAs dependent regulation of DNMT and HIF1α gene expression in thrombotic disorders

“…VEGF, Hypoxia, and Angiogenesis pathway, on the other hand, is involved in interaction between cancer and thrombosis 56 . Next, the TPO Signaling Pathway is associated with megakaryopoiesis- a process involving hematopoietic stem cells to generate megakaryocyte followed by the production of platelets 57 .…”

Electroacupuncture Regulates Pain Transition Through Inhibiting PKCε and TRPV1 Expression in Dorsal Root Ganglion

“…However, PKCε not only is responsible for the pain transition but also contributes to various physiological functions ( Chen and Tian, 2011 ; Kostyak et al, 2017 ). Its various roles present a particularly challenging problem, requiring clinicians to balance two competing interests: preventing the transition from acute to chronic pain and minimizing interference with physiological functions.…”