p-Y546,Y584-PTPN11 (in CSF3 dimer:2xp-4Y-CSF3R:LYN:p-Y-JAK1:p-JAK2:p-SYK:p-HCK:p-TYK2:SHC:GRB2:PTPN11) dephosphorylates KRAS

Stable Identifier
Reaction [transition]
Homo sapiens
Locations in the PathwayBrowser
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CSF3 (G-CSF) signaling activates ERKs (ERK1, ERK2) via RAS. One possible mechanism of RAS activation is the dephosphorylation of KRAS (the dominant isoform of RAS in hematopoietic cells) by phosphorylated PTPN11 (also known as SHP-2 or SHP2) (Kano et al. 2019) bound to phosphorylated CSF3R. Dephosphorylation of RAS increases the association of RAS with its downstream effector RAF. Inhibition of PTPN11 in mouse cells indicates that this pathway accounts for most but not all activation of ERKs in response to CSF3 (Jack et al. 2009, Zhang and Friedman 2011). Guanyl nucleotide exchange factors SOS or VAV bound to GRB2 may also be responsible for some activation of RAS in response to CSF3, but this has not yet been demonstrated.

Literature References
PubMed ID Title Journal Year
30644389 Tyrosyl phosphorylation of KRAS stalls GTPase cycle via alteration of switch I and II conformation

Kano, Y, Gebregiworgis, T, Marshall, CB, Radulovich, N, Poon, BPK, St-Germain, J, Cook, JD, Valencia-Sama, I, Grant, BMM, Herrera, SG, Miao, J, Raught, B, Irwin, MS, Lee, JE, Yeh, JJ, Zhang, ZY, Tsao, MS, Ikura, M, Ohh, M

Nat Commun 2019
21725048 SHP2 tyrosine phosphatase stimulates CEBPA gene expression to mediate cytokine-dependent granulopoiesis

Zhang, L, Friedman, AD

Blood 2011
19587381 M-CSF elevates c-Fos and phospho-C/EBPalpha(S21) via ERK whereas G-CSF stimulates SHP2 phosphorylation in marrow progenitors to contribute to myeloid lineage specification

Jack, GD, Zhang, L, Friedman, AD

Blood 2009
Catalyst Activity

protein tyrosine phosphatase activity of CSF3 dimer:2xp-4Y-CSF3R:LYN:p-Y-JAK1:p-JAK2:p-SYK:p-HCK:p-TYK2:p-Y-SHC1:GRB2:p-Y643-GAB2:p-Y546,Y584-PTPN11 [plasma membrane]

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