Erk1^R84H is an oncoprotein that causes hepatocellular carcinoma in mice and imposes a rigorous negative feedback loop

The receptor tyrosine kinase (RTK)-Ras-Raf-MEK-Erk cascade is frequently mutated in cancer, but it is not known whether Erk is a sole mediator of the pathway’s oncogenicity, and what degree of Erk activity is required for oncogenicity. Also, it is assumed that high Erk activity is required to impose and maintain oncogenicity, but the exact degree of required activity is not clear. We report that induced expression of the intrinsically active variant Erk1^R84H in mouse liver gave rise to hepatocellular carcinoma (HCC). Intriguingly, the phosphorylated/active form of Erk1^R84H was dramatically downregulated during HCC development, and became almost undetectable in mature tumors. Similarly, in Erk1^R84H-transformed NIH3T3 cells, the phosphorylated/active form of Erk1^R84H was undetectable. Thus, 1) Erk1 could by itself cause HCC in mice, suggesting that it is the major or even the sole mediator of the cascade’s oncogenicity. 2) Erk1^R84H-induced tumors (and other tumors) are maintained by a minimal Erk activity. 3) Erk1^R84H is probably the driver of the malignancy in patients that carry the R84H mutation.