Growth factor pleiotropy is controlled by a receptor Tyr/Ser motif that acts as a binary switch

Abstract

Pleiotropism is a hallmark of cytokines and growth factors; yet, the underlying mechanisms are not clearly understood. We have identified a motif in the granulocyte macrophage-colony-stimulating factor receptor composed of a tyrosine and a serine residue that functions as a binary switch for the independent regulation of multiple biological activities. Signalling occurs either through Ser585 at lower cytokine concentrations, leading to cell survival only, or through Tyr577 at higher cytokine concentrations, leading to cell survival as well as proliferation, differentiation or functional activation. The phosphorylation of Ser585 and Tyr577 is mutually exclusive and occurs via a unidirectional mechanism that involves protein kinase A and tyrosine kinases, respectively, and is deregulated in at least some leukemias. We have identified similar Tyr/Ser motifs in other cell surface receptors, suggesting that such signalling switches may play important roles in generating specificity and pleiotropy in other biological systems.

14-3-3:Shc Scaffolds Integrate Phosphoserine and Phosphotyrosine Signaling to Regulate Phosphatidylinositol 3-Kinase Activation and Cell Survival

“…Tyr 179 of 14-3-3 Is Important for the Assembly of a PI 3-Kinase Signaling Complex in Response to Cytokine-Our findings, as well as those of others, have shown that both 14-3-3 and Shc are important for the regulation of PI 3-kinase signaling in response to GM-CSF (10,12,18). We therefore examined the possibility that the binding of Shc to Tyr 179 of 14-3-3 in response to GM-CSF stimulation may be necessary for the assembly of an active PI 3-kinase signaling complex.…”

“…We have previously shown that there are two distinct cell survival pathways emanating from the ␤c subunit of the GM-CSF receptor: one that promotes ␤cSer 585 phosphorylation and 14-3-3 binding and the other that promotes ␤cTyr 577 phosphorylation and Shc binding (9,10). This raised the possibility that 14-3-3 and Shc may form part of a ␤c receptor-proximal signaling scaffold involved in regulating cytokine function.…”

“…The myelomonocytic UT7 factordependent cell line was cultured in RPMI and 10% FCS supplemented with 2 ng/ml GM-CSF. Mononuclear cells were purified from normal donors as previously described (10). CTL-EN and UT7 cells were electroporated with constructs for the expression of 14-3-3-Myc (20 g), Akt-HA (5 g), and/or ERK-HA (5 g).…”

“…Our previous results showed that the ␤c subunit of the GM-CSF receptor is able to promote PI 3-kinase activation via two pathways; one pathway is regulated via Tyr 577 of ␤c, which binds Shc, and the other pathway is regulated via Ser 585 of ␤c, which binds 14-3-3 (9, 10, 12). Importantly, although no reduction in cell survival or proliferation in response to high concentrations of cytokine (Ͼ10 pM) was observed in either the Y577F or the S585G single mutants, these biological responses were defective in the Y577F/S585G double mutant (9,10,12). Thus, our results indicated that Tyr 577 could compensate for the loss of Ser 585 , whereas Ser 585 could compensate for the loss of Tyr 577 .…”

Critical Evaluation of Antiepileptic Drugs in Epileptic Pregnant Women - Hungarian Experiences

“…Y577, Y612 and Y695 in JAK-2 were sufficient to signal proliferation. Observations in human GM-CSF responsive cell lines identified that phosphorylation of a conserved serine residue, S585, was critical for suppressing apoptosis, particularly at limiting concentrations of cytokine [42]. At low doses cells survived but did not proliferate and ßc was phosphorylated at S585 but not at Y577.…”