The active component of ginseng, ginsenoside Rb1, improves erythropoiesis in models of Diamond–Blackfan anemia by targeting Nemo-like kinase

Abstract

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Signaling Pathways That Regulate Normal and Aberrant Red Blood Cell Development

“…Despite being highly influenced by kinases, relatively few erythropoiesis deficiencies are currently attributed to deregulated kinase activity. The most characterized of these are pyruvate kinase, DYRK3, mTORC1, p38/JNK, and NLK [21][22][23]25,[59][60][61].…”

“…Many of these kinase-signaling cascades are well characterized and include Janus kinase/signal transducer and activator of transcription (JAK/STATs), PI3K/Akt, and mitogen-activated protein kinases (MAPKs). In many diseases, it is not the direct deregulation of one of these kinases but rather aberrant deregulation of another kinase that negatively feeds back into the signals initiated by the hematopoietic cytokines [20][21][22][23][24][25][26][27]. While these phosphorylate normally unphosphorylated substrates to trigger pathogenic signals, they frequently disrupt homeostatic pathways.…”

“…Perhaps the most characterized of these is the activation of the tyrosine kinase cellular Abelson tyrosine kinase (c-Abl) associated with the Philadelphia chromosome fusion event in chronic myeloid leukemia (CML) [28]. Of particular relevance to ribosomopathies, the relatively under-characterized atypical MAPK kinase Nemo-like kinase (NLK) has been shown to be chronically activated in early erythroid progenitors and contributes to the disease phenotype [21][22][23]. Our understanding of how NLK deregulates erythropoiesis is rudimentary but most likely provides only an initial insight into the disrupted kinase network responsible for controlled, healthy red blood cell production.…”

“…As with Bcr-Abl, kinases are readily druggable pharmacological targets and are the most successfully targeted class of proteins in medicinal chemistry [6]. Evidence is beginning to emerge that disruption of kinase homeostasis in the erythroid progenitors of DBA patients is contributing to disease pathogenesis [21][22][23]. NLK has overlapping substrate specificity with a number of MAPK members activated in early erythropoiesis and suppression of NLK expression [21][22][23] or activity [21] improves erythroid expansion.…”

“…Evidence is beginning to emerge that disruption of kinase homeostasis in the erythroid progenitors of DBA patients is contributing to disease pathogenesis [21][22][23]. NLK has overlapping substrate specificity with a number of MAPK members activated in early erythropoiesis and suppression of NLK expression [21][22][23] or activity [21] improves erythroid expansion. Some substrates have been identified in these cells, but understanding the novel pathways initiated, as well as how it disrupts existing pathways, is likely to shed significant insight into our understanding of DBA.…”