MYC/MAX control ERK signaling and pluripotency by regulation of dual-specificity phosphatases 2 and 7

Suppression of extracellular signal-regulated kinase (ERK) signaling is an absolute requirement for the maintenance of murine pluripotent stem cells (mPSCs) and requires the MYC-binding partner MAX. In this study, we define a mechanism for this by showing that MYC/MAX complexes suppress ERK activity by transcriptionally regulating two members of the dual-specificity phosphatase (DUSP) family. DUSPs function by binding and then inactivating ERK1,2 by dephosphorylating residues required for catalytic activity. MYC/MAX complexes achieve this by binding the promoters of DUSP2 and DUSP7, leading to their transcriptional activation, resulting in the attenuation of ERK activity. In the absence of MYC, ectopic DUSP2,7 expression severely delays differentiation, while loss of DUSP2,7 ectopically activates ERK, resulting in loss of pluripotency. These findings elucidate a novel regulatory role for MYC in PSC maintenance involving the stimulation of phosphatases that directly inhibit the MAPK/ERK signaling pathway. Moreover, it provides a mechanism for how leukemia inhibitory factor (LIF)/STAT3 signaling reaches across to the MAPK/ERK pathway through MYC and MAX to sustain pluripotency.