Granulocyte colony-stimulating factor receptor signaling in severe congenital neutropenia, chronic neutrophilic leukemia, and related malignancies  Pankaj Dwivedi, Kenneth D. Greis  Experimental Hematology  Volume 46, Pages 9-20 (February 2017) DOI: 10.1016/j.exphem.2016.10.008 Copyright © 2016 ISEH - International Society for Experimental Hematology Terms and Conditions

Experimental Hematology 2017 46, 9-20DOI: (10.1016/j.exphem.2016.10.008) Copyright © 2016 ISEH - International Society for Experimental Hematology Terms and Conditions

Figure 1 Topography of G-CSFR depicting various structural domains and the mutations associated with specific domains leading to neutropenia and leukemia. Experimental Hematology 2017 46, 9-20DOI: (10.1016/j.exphem.2016.10.008) Copyright © 2016 ISEH - International Society for Experimental Hematology Terms and Conditions

Figure 2 Major downstream signaling pathways of normal and variant G-CSFR. (A) In normal G-CSFR, the major pathways activated downstream of the receptor are JAK/STAT, PI3K/AKT, and MAPK/ERK, whereas SOCS acts as negative regulator of the overall signaling. (B) G-CSFR with a mutated extracellular receptor leads to disruption of G-CSF binding, causing the cessation of downstream signaling. (C) Proximally mutated receptor becomes auto-activated and facilitates constitutive activation of the downstream pathways even in the absence of ligand. (D) Several truncations in the cytoplasmic domains of G-CSFR lead to hyperresponse to G-CSF and uncontrolled signaling downstream of the receptor on ligand binding. Experimental Hematology 2017 46, 9-20DOI: (10.1016/j.exphem.2016.10.008) Copyright © 2016 ISEH - International Society for Experimental Hematology Terms and Conditions

Figure 3 G-CSFR routing and recycling. (A) In the wild-type receptor, G-CSF-induced activation leads to receptor internalization and endosome formation. Although the receptor is internalized, downstream signaling continues. After this point, the receptor has two modes to move forward: it either is dephosphorylated and deubiquitinated, further processed in endoplasmic reticulum and Golgi, and recycled to plasma membrane, or it transitions into the late endosome and is degraded by the lysosomal pathway. (B) In membrane proximally mutated receptors, it is postulated that the recycling rate is increased with rapid processing through endoplasmic reticulum and Golgi. (C) In cases where the mutation results in intracellular domain truncation, the receptor recycling/degradation process is disrupted because of loss of the motif required for endocytic signaling. This leads to increased receptor expression on the plasma membrane and sustained downstream signaling. Experimental Hematology 2017 46, 9-20DOI: (10.1016/j.exphem.2016.10.008) Copyright © 2016 ISEH - International Society for Experimental Hematology Terms and Conditions

Figure 4 Possible roles played by kinases and phosphatases in overall G-CSFR signaling and their decisive effects on myeloid cell production and neutrophils. Experimental Hematology 2017 46, 9-20DOI: (10.1016/j.exphem.2016.10.008) Copyright © 2016 ISEH - International Society for Experimental Hematology Terms and Conditions