Signaling by CSF3 (G-CSF)

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Homo sapiens
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CSF3 (GCSF) is a cytokine that regulates production of neutrophils and granulocytes (reviewed in Panopoulos and Watowich 2008). CSF3 circulates extracellularly as a dimer and binds to the monomeric receptor CSF3R (GCSFR) on neutrophil precursors and mature neutrophils (reviewed in Futosi et al. 2013). CSF3R possesses no catalytic activity of its own and is constitutively associated with the kinases LYN (Corey et al. 1994) and JAK1 (Nicholson et al. 1994). Upon binding the CSF3 dimer, CSF3R dimerizes, is phosphorylated, and activates JAK-STAT signaling, RAS-RAF-MEK-ERK signaling, and PI3K signaling (reviewed in Basu et al. 2002, Roberts et al. 2005, Kendricks and Bogoyevitch 2007, Touw and van de Geijn 2007).
After dimerization of CSF3R, JAK1 associated with CSF3R is required for phosphorylation of tyrosine residues in the cytosolic domain of CSF3R which recruit further kinases such as JAK2, SYK, HCK, and TYK2 (reviewed in Sampson et al. 2007). Phosphorylated JAK1 and JAK2 then appear to act redundantly to phosphorylate STAT proteins (STAT1, STAT3, STAT5) which dimerize and transit to the nucleus to activate gene expression.
CSF3 signaling also activates the RAS pathway, resulting in activation of ERK1 and ERK2 and cellular proliferation. Phosphorylated CSF3R recruits both GRB2, which can act as a scaffold for RAS guanyl exchange factors SOS and VAV, and PTPN11 (SHP2), which activates RAS by dephosphorylating tyrosine-32 of RAS (Bunda et al. 2015). Association of SOS or VAV with the phosphorylated CSF3R has not yet been shown. The pathway to activation of PI3K is uncertain but appears to proceed via GAB2 bound to CSF3R.
Mutations in CSF3R can occur during the course of Kostmann disease, a severe congenital neutropenia (reviewed in Zeidler and Welte 2002, Zeidler 2005, Ward 2007, Vandenberghe and Beel 2011). Somatic mutations in CSF3R, principally truncations of the C-terminal region, are involved in the pathogenesis of severe congenital neutropenia and are associated with progression to acute myeloid leukemia (Dong et al. 1995, reviewed in Ward 2007, Beekman and Touw 2010, Xing and Zhao 2016). Loss or mutation of the C-terminal region of CSF3R interferes with inhibition and turnover of the receptor. Mutation of Thr-618 to Ile-618 in CSF3R causes spontaneous dimerization and consequent autoactivation leading to CSF3-independent signaling and chronic neutrophilic leukemia (Maxson et al. 2013).

Literature References
PubMed ID Title Journal Year
17127394 Src kinases in G-CSF receptor signaling

Corey, SJ, Zhu, QS, Sampson, M

Front. Biosci. 2007
7512720 Tyrosine kinase JAK1 is associated with the granulocyte-colony-stimulating factor receptor and both become tyrosine-phosphorylated after receptor activation

Oates, AC, Ziemiecki, A, Layton, JE, Nicholson, SE, Wilks, AF, Harpur, AG

Proc. Natl. Acad. Sci. U.S.A. 1994
20237318 G-CSF and its receptor in myeloid malignancy

Touw, IP, Beekman, R

Blood 2010
18400509 Granulocyte colony-stimulating factor: molecular mechanisms of action during steady state and 'emergency' hematopoiesis

Panopoulos, AD, Watowich, SS

Cytokine 2008
26956865 Colony Stimulating Factor 3 Mutations and Myeloid Malignancies

Zhao, MF, Xing, Y

Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2016
26617336 Inhibition of SHP2-mediated dephosphorylation of Ras suppresses oncogenesis

Ohh, M, Zeng, L, Zadeh, G, Bunda, S, Raught, B, Burrell, K, Kano, Y, Alamsahebpour, A, Zhang, ZY, Heir, P

Nat Commun 2015
16019425 G-CSF: a key regulator of neutrophil production, but that's not all!

Roberts, AW

Growth Factors 2005
17127322 The role of the granulocyte colony-stimulating factor receptor (G-CSF-R) in disease

Ward, AC

Front. Biosci. 2007
16188692 Congenital neutropenias

Zeidler, C

Hematology 2005
11957189 Kostmann syndrome and severe congenital neutropenia

Welte, K, Zeidler, C

Semin. Hematol. 2002
17127321 Granulocyte colony-stimulating factor and its receptor in normal myeloid cell development, leukemia and related blood cell disorders

van de Geijn, GJ, Touw, IP

Front. Biosci. 2007
8197119 Granulocyte colony-stimulating factor receptor signaling involves the formation of a three-component complex with Lyn and Syk protein-tyrosine kinases

Corey, SJ, Tweardy, DJ, Bolen, JB, Tkatch, LS, Burkhardt, AL, Geahlen, RL

Proc. Natl. Acad. Sci. U.S.A. 1994
23656643 Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML

Eide, CA, Bottomly, D, Fleischman, AG, Goueli, B, Tyner, JW, Chang, BH, Oh, ST, Deininger, MW, Pond, JB, Loriaux, MM, Pollyea, DA, Tognon, CE, Druker, BJ, McWeeney, SK, Wilmot, B, Collins, RH, Gotlib, J, Maxson, JE, Agarwal, A

N Engl J Med 2013
12060844 G-CSF: function and modes of action (Review)

Dunn, A, Basu, S, Ward, A

Int. J. Mol. Med. 2002
7542747 Mutations in the gene for the granulocyte colony-stimulating-factor receptor in patients with acute myeloid leukemia preceded by severe congenital neutropenia

Touw, IP, Tidow, N, Löwenberg, B, Dong, F, Brynes, RK, Welte, K

N Engl J Med 1995
17127320 Activation of mitogen-activated protein kinase pathways by the granulocyte colony-stimulating factor receptor: mechanisms and functional consequences

Kendrick, TS, Bogoyevitch, MA

Front. Biosci. 2007
23994464 Neutrophil cell surface receptors and their intracellular signal transduction pathways

Futosi, K, Mócsai, A, Fodor, S

Int. Immunopharmacol. 2013
22053285 Severe congenital neutropenia, a genetically heterogeneous disease group with an increased risk of AML/MDS

Vandenberghe, P, Beel, K

Pediatr Rep 2011
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