G-CSF receptor activation of the Src kinase Lyn is mediated by Gab2 recruitment of the Shp2 phosphatase

Abstract

Src activation involves the coordinated regulation of positive and negative tyrosine phosphorylation sites. The mechanism whereby receptor tyrosine kinases, cytokine receptors, and integrins activate Src is not known. Here, we demonstrate that granulocyte colony-stimulating factor (G-CSF) activates Lyn, the predominant Src kinase in myeloid cells, through Gab2-mediated recruitment of Shp2. After G-CSF stimulation, Lyn dynamically associates with Gab2 in a spatiotemporal manner. The dephosphorylation of phospho-Lyn Tyr507 was abrogated in Shp2-deficient cells transfected with the G-CSF receptor but intact in cells expressing phosphatase-defective Shp2. Auto-phosphorylation of Lyn Tyr396 was impaired in cells treated with Gab2 siRNA. The constitutively activated Shp2E76A directed the dephosphorylation of phospho-Lyn Tyr507 in vitro. Tyr507 did not undergo dephosphorylation in G-CSF–stimulated cells expressing a mutant Gab2 unable to bind Shp2. We propose that Gab2 forms a complex with Lyn and after G-CSF stimulation, Gab2 recruits Shp2, which dephosphorylates phospho-Lyn Tyr507, leading to Lyn activation.

CSF3R mutations have a high degree of overlap with CEBPA mutations in pediatric AML

“…Hematopoietic cell transplantation (HCT) is a possible treatment, but systematic outcome data are lacking, due to the use of different eligibility criteria and protocols worldwide. [4][5][6][7][8][9][10][11][12] In order to assess HCT efficacy, we evaluated all 35 consecutive MLD patients presenting between 2004 and 2015 in our department, the Dutch Leukodystrophy Referral Center ( Figure 1A).…”

SH2 Domain-Containing Phosphatase 2 Is a Critical Regulator of Connective Tissue Mast Cell Survival and Homeostasis in Mice

“…Src kinase also localizes to mitochondria and regulates cytochrome c oxidase activity in osteoclasts (33,39). SHP2 can promote the activation of Src family kinases via dephosphorylating inhibitory C-terminal phosphorylation sites directly (16) and indirectly by blocking recruitment of C-terminal Src kinase (12). Whether SHP2 regulates the phosphorylation of mitochondrial proteins directly in mast cells will require further studies.…”

“…In postmitotic neurons, SHP2 regulates energy balance and early-onset obesity (26,49), whereas in neural stem cells, SHP2 KO results in defective differentiation and early postnatal lethality (23). SHP2 is essential for the survival of hematopoietic stem cells in mice (10,16). Conversely, expression of human juvenile myelomonocytic leukemia (JMML)-associated shp2 mutants in mouse hematopoietic stem/progenitor cells results in the development of a fatal JMML-like disorder (34,46).…”

Alternatively spliced, truncated GCSF receptor promotes leukemogenic properties and sensitivity to JAK inhibition

“…Grb2 couples to both Gab2 and to SOS, permitting signaling diversification involving Ras/ERK, phosphatidylinositol 3-kinase/Akt and Src homology 2 phosphatase (SHP-2). 21,22 Negative regulatory molecules, Src homology 2 domain containing inositol 5′-phosphatase and cytokine inducible Src homology 2 protein, are recruited to the GCSFR at residues 744 and 764. 23 The class IV isoform lacks three of the four tyrosine residues (Y729, Y744, Y764) in the distal domain.…”