Αρχειοθήκη ιστολογίου

Τρίτη 13 Φεβρουαρίου 2018

Small molecule-mediated activation of RAS elicits biphasic modulation of phospho ERK levels that are regulated through negative feedback on SOS1

Oncogenic mutation of RAS results in aberrant cellular signaling and is responsible for more than 30% of all human tumors. Therefore, pharmacological modulation of RAS has attracted great interest as a therapeutic strategy. Our laboratory has recently discovered small molecules that activate Son of Sevenless (SOS)-catalyzed nucleotide exchange on RAS and inhibit downstream signaling. Here we describe how pharmacologically targeting SOS1 induced biphasic modulation of RAS-GTP and ERK phosphorylation levels, which we observed in a variety of cell lines expressing different RAS mutant isoforms. We show that compound treatment caused an increase in phosphorylation at ERK consensus motifs on SOS1 that was not observed with the expression of a non-phosphorylatable S1178A SOS1 mutant or after pretreatment with an ERK inhibitor. Phosphorylation at S1178 on SOS1 is known to inhibit the association between SOS1 and GRB2 and disrupt SOS1 membrane localization. Consistent with this, we show that wild-type SOS1 and GRB2 dissociated in a time dependent fashion in response to compound treatment, and conversely, this interaction was enhanced with the expression of a S1178A SOS1 mutant. Furthermore, in cells expressing either S1178A SOS1 or a constitutively membrane-bound CAAX box tagged SOS1 mutant, we observed elevated RAS-GTP levels over time in response to compound, as compared to the biphasic changes in RAS-GTP exhibited in cells expressing wild-type SOS1. These results suggest that small molecule targeting of SOS1 can elicit a biphasic modulation of RAS-GTP and phospho ERK levels through negative feedback on SOS1 that regulates the interaction between SOS1 and GRB2.



from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2CiTQCi

Δεν υπάρχουν σχόλια:

Δημοσίευση σχολίου