ERK phosphorylates HNRNPF to promote the proliferation and suppress the differentiation of embryonic stem cells.

The mitogen-activated extracellular signal-regulated kinase/extracellular signal-regulated kinase (MEK/ERK) signaling plays a dual role in regulating the self-renewal and differentiation of embryonic stem cells (ESCs). How MEK/ERK promotes ESC self-renewal remains elusive, while the mechanisms for MEK/ERK to stimulate ESC differentiation have been investigated extensively. Here, we demonstrated that ERK2 phosphorylates heterogenous nuclear ribonucleoprotein F (HNRNPF) on Ser346 and Tyr356. Hnrnpf knockout reduces ESC proliferation rate, through downregulating CDK1 and CCNB1, and promotes ESC differentiation, attributed to reduced EED. Moreover, compared with the unphospho-mimetic mutant, the phospho-mimetic HNRNPF is more potent in rescuing ESC growth, as well as suppressing the mesodermal and trophectodermal differentiation. Mechanistically, HNRNPF binds to Cdk1, Ccnb1, and Eed messenger RNAs (mRNAs), thereby enhancing their translation efficiency. Additionally, phosphorylation of HNRNPF enhances its binding to these mRNAs and promotes their translation. Taken together, ERK may facilitate ESC proliferation and suppress lineage differentiation through phosphorylating HNRNPF.