The MEK1 inhibitors UO126 and PD98059 block PDGF-AB induced phosphorylation of threonine 292 in porcine smooth muscle cells


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Abstract

HighlightsPDGF-AB induces smooth muscle cell proliferation via activation of MEK1/2.Activation of MEK1/2 depends on the phosphorylation status.MEK1/2 inhibitors UO126 and PD98059 (INH) downregulate proliferation.INH reduce phosphorylation (P-) of Thr292 of MEK1 and increase P-Ser218/222.Downregulation of P-Thr292 and increase of P-Ser218/222 might be an “off” switch.PDGF-AB and FGF-2 (GFs) induce smooth muscle cell (SMC) proliferation which is indispensible for arteriogenesis. While there is common agreement that GFs stimulate SMC proliferation through phosphorylation (P-) of MEK1/2 at Ser218/222, we previously demonstrated that the MEK inhibitors PD98059 and UO126 did not inhibit P-Ser218/222 as originally proposed but caused strong hyperphosphorylation. Here, we demonstrate that GFs increased phosphorylation of MEK1 at Thr292 while UO126 and PD98059 blocked this phosphorylation. This was again surprising since phosphorylation of Thr292 is regarded as a negative feedback loop. Our findings suggest that inhibition of Thr292 phosphorylation in combination with hyperphosphorylation of Ser218/222 serves as an “off” switch of SMC proliferation and potentially of arteriogenesis.

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