EGF induced SOS phosphorylation in PC12 cells involves P90 RSK-2

Abstract

SOS, the guanine nucleotide exchange factor for Ras, becomes phosphorylated on serine and threonine residues following stimulation of cells with growth factors. These phosphorylations may play a role in negative feedback of Ras stimulation and have been shown to be mediated in part by the MAP kinases Erk-1 and Erk-2. Here we show that in addition to MAP kinase, a major mitogen activated kinase for SOS is p90 Rsk-2, a downstream target of MAP kinase. p90 Rsk-2 phosphorylates SOS in an in gel assay and also in solution in vitro. The ability of p90 Rsk-2 to phosphorylate SOS increases greatly following EGF treatment of PC12 cells and is blocked by expression of N17 Ras or treatment with the MEK inhibitor PD98059. Phosphopeptide mapping revealed that the sites phosphorylated by p90 Rsk-2 in vitro were also phosphorylated in intact cells in response to EGF treatment. Several major sites of in vivo phosphorylation correlated with p90 Rsk-2 phosphorylation sites rather than MAP kinase sites. It is therefore likely that p90 Rsk-2 plays an important role in the down regulation of the Ras activation pathway through SOS.

RPS6KA2, a putative tumour suppressor gene at 6q27 in sporadic epithelial ovarian cancer

“…Interestingly, RPS6KA6, a related member of the family, inhibits the MAP kinase pathway (Myers et al, 2004). RPS6KA3 has also been shown to inhibit MAP kinase cascade by negative feedback at the level of SOS (Douville and Downward, 1997). Although the effects observed on the cell cycle proteins are similar to that observed by another bona fide tumour suppressor gene p16, the results are not conclusive.…”

Negative feedback via RSK modulates Erk‐dependent progression from naïve pluripotency

“…Increased pERK was also found in skeletal tissue of RSK2‐deficient mice 75. Biochemically, reduction in pERK by RSKs is thought to be mediated through phosphorylation of SOS 52. A possible mechanism has been suggested whereby phosphorylated SOS1 binds to 14‐3‐3 proteins, resulting in reduced activity of SOS1 or prevention of its interaction with the signalling complex 54.…”

Complexity of Receptor Tyrosine Kinase Signal Processing

“…Upon RTK activation, the SOS-Grb2 complex is recruited to the plasma membrane where SOS mediates Ras activation. SOS phosphorylation by ERK or by its downstream kinase RSK-2 leads to dissociation of the SOS -Grb2 complex, thereby terminating Ras activation (Langlois et al 1995;Dong et al 1996;Douville and Downward 1997).…”