DUSP5 and DUSP6, two ERK specific phosphatases, are markers of a higher MAPK signaling activation in BRAF mutated thyroid cancers

Abstract

BackgroundMolecular alterations of the MAPK pathway are frequently observed in papillary thyroid carcinomas (PTCs). It leads to a constitutive activation of the signalling pathway through an increase in MEK and ERK phosphorylation. ERK is negatively feedback-regulated by Dual Specificity Phosphatases (DUSPs), especially two ERK-specific DUSPs, DUSP5 (nuclear) and DUSP6 (cytosolic). These negative MAPK regulators may play a role in thyroid carcinogenesis.MethodsMAPK pathway activation was analyzed in 11 human thyroid cancer cell lines. Both phosphatases were studied in three PCCL3 rat thyroid cell lines that express doxycycline inducible PTC oncogenes (RET/PTC3, H-RASV12 or BRAFV600E). Expression levels of DUSP5 and DUSP6 were quantified in 39 human PTCs. The functional role of DUSP5 and DUSP6 was investigated through their silencing in two human BRAFV600E carcinoma cell lines.ResultsBRAFV600E human thyroid cancer cell lines expressed higher phospho-MEK levels but not higher phospho-ERK levels. DUSP5 and DUSP6 are specifically induced by the MEK-ERK pathway in the three PTC oncogenes inducible thyroid cell lines. This negative feedback loop explains the tight regulation of p-ERK levels. DUSP5 and DUSP6 mRNA are overexpressed in human PTCs, especially in BRAFV600E mutated PTCs. DUSP5 and/or DUSP6 siRNA inactivation did not affect proliferation in two BRAFV600E mutated cell lines, which may be explained by a compensatory increase in other phosphatases. In the light of this, we observed a marked DUSP6 upregulation upon DUSP5 inactivation. Despite this, DUSP5 and DUSP6 positively control cell migration and invasion.ConclusionsOur results are in favor of a stronger activation of the MAPK pathway in BRAFV600E PTCs. DUSP5 and DUSP6 have pro-tumorigenic properties in two BRAFV600E PTC cell line models.

Precision Targeted Therapy with BLU-667 for RET-Driven Cancers

“…2A-C ). To confi rm MAPK pathway suppression, we measured the impact of BLU-667 on expression of DUSP6 and SPRY4 , two genes transcriptionally regulated by ERK1/2 ( 32,33 ). In all models tested, regardless of lineage or type of RET alteration, BLU-667 decreased the abundance of these transcripts in a dosedependent manner but did not affect the expression of GSK3B , a component of the parallel PI3K-AKT pathway ( Fig.…”

Profiling of Y1 Cells Treated With FGF-2 Reveals Parallels With Oncogene-Induced Senescence

“…6 and Table 3). The induction of DUSP expression may act as a negative feedback mechanism in response to elevated MEK/MAPK activity, as seen in models of thyroid cancer with mutant BRAF (Buffet et al, 2017). Another study found that Dusp5 is a transcriptional target of p53, and as expected, DNA damage is able to drive p53-dependent expression of Dusp5 (Ueda et al, 2003).…”

The iPSC proteomic compendium

“…MLKs can phosphorylate and activate MEK, with MLK1 and MLK3 being the most effective at activating ERK 43 . We also see an increase in the nuclear ERK phosphatase DUSP5, which is activated as a negative feedback control for ERK 44 and PAK5, a constitutively active kinase that can phosphorylate BAD to prevent apoptosis 45 .…”