Extracellular Signal-Regulated Kinases 1 and 2 Phosphorylate Gab2 To Promote a Negative-Feedback Loop That Attenuates Phosphoinositide 3-Kinase/Akt Signaling

Abstract

The scaffolding adapter protein Gab2 (Grb2-associated binder) promotes cell proliferation, survival, and motility by engaging several signaling pathways downstream of growth factor and cytokine receptors. In particular, Gab2 plays essential roles in mast cells, as it is required for phosphoinositide 3-kinase (PI3K) activation in response to Kit and the high-affinity IgE receptor. While the positive role of Gab2 in PI3K signaling is well documented, very little is known about the mechanisms that attenuate its function. Here we show that Gab2 becomes phosphorylated on multiple proline-directed sites upon stimulation of the Ras/extracellular signal-regulated kinase (ERK) signaling pathway. We demonstrate that ERK1 and ERK2 interact with Gab2 via a novel docking motif, which is required for subsequent Gab2 phosphorylation in response to ERK1/2 activation. We identified four ERK1/2-dependent phosphorylation sites in Gab2 that prevent the recruitment of the p85 regulatory subunit of PI3K. Using bone marrow-derived mast cells to study Gab2-dependent signaling, we found that the inhibition of ERK1/2 activity promotes Akt signaling in response to Kit and the high-affinity IgE receptor. Together, our results indicate that ERK1/2 participates in a negative-feedback loop that attenuates PI3K/Akt signaling in response to various agonists.

PTEN Is Required for The Anti-Epileptic Effects of AMPA Receptor Antagonists in Chronic Epileptic Rats

“…Gab2 becomes tyrosine-phosphorylated in response to a variety of growth factors and forms multimolecular complexes with SH2 domain-containing signaling molecules [48]. Indeed, p97/Gab2 is required for the PI3K/AKT1 signaling pathway [49] and p97/Gab2-mediated PI3K/AKT1 activation is involved in the pathogenesis of Alzheimer's disease (AD) [50] that shows the reduced GRIA1 surface expression [51]. However, p97/Gab2 protein expression is remarkably reduced in the hippocampus of TLE patients and chronic epileptic rats [52].…”

RSK Regulates PFK-2 Activity to Promote Metabolic Rewiring in Melanoma

“…All cell lysates were prepared as previously described (38). Briefly, cells were washed 3 times with ice-cold PBS and lysed in BLB [10 mmol/L K 3 PO 4 , 1 mmol/L EDTA, 5 mmol/L EGTA, 10 mmol/L MgCl 2 , 50 mmol/L b-glycerophosphate, 0.5% Nonidet P-40, 0.1% Brij 35, 0.1% deoxycholic acid, 1 mmol/L sodium orthovanadate (Na 3 VO 4 ), 1 mmol/L phenylmethylsulfonyl fluoride, and a cOmplete protease inhibitor cocktail tablet (Roche)].…”

G‐CSF‐dependent neutrophil differentiation requires downregulation of MAPK activities through the Gab2 signaling pathway

“…The down-regulations of tyrosine phosphorylation of Gab2 following stimulation of growth factors or cytokines have been reported previously (Lynch and Daly, 2002;Zhang et al, 2013;Zhang et al, 2017). In human adenocarcinoma cell line MCF-7, heregulinactivated ErbB receptor induced tyrosine phosphorylation of Gab2 leading to the activation of Ras-MAPK signaling as well as the PI-3K-Akt signaling.…”