Seminar "Aberrant post-translational modifications of the MEK MAPKK in cancer" Prof. Mutsuhiro Takekawa.
Speaker: Mutsuhiro Takekawa
Div. of Cell Signaling and Molecular Medicine,
Institute of Medical Science, The University of Tokyo
Title: Aberrant post-translational modifications of the MEK MAPKK in cancer
Abstract: The RAS-ERK MAPK cascade (Raf-MEK-ERK) is activated by mitogenic stimuli and is generally associated with cell proliferation and malignant transformation. This pathway is frequently hyper-activated by various oncogenes such as Ras, and Raf in human cancers. Here, we report that the ERK pathway is down-regulated by MEK sumoylation, which is inhibited by oncogenic Ras. We show that MEK sumoylation blocks ERK activation by disrupting the specific docking interaction between MEK and ERK. Expression of an unsumoylatable MEK mutant enhances ERK activation, cell proliferation, and malignant transformation by oncogenic ErbB2 or Raf, but not by active Ras. Interestingly, MEK sumoylation is abrogated in cancer cells harboring Ras mutations. Oncogenic Ras inhibits MEK sumoylation by impairing the MEK-specific Sumo E3 ligase activity of MEKK1. Furthermore, forced enhancement of MEK sumoylation suppresses Ras-induced cell transformation. Thus, oncogenic Ras efficiently activates the ERK pathway not only by activating Raf but also by inhibiting MEK sumoylation, thereby inducing carcinogenesis.
Recently, more than 20 different mutations in the MEK1/2 genes have been identified in sporadic cancers and the cancer-prone congenital syndromes (the Ras-MAPK syndromes). The Ras-MAPK syndromes are genetic disorders that include symptoms such as mental retardation, facial dysmorphisms, heart defects, developmental delay, and an increased risk of developing cancer. In this talk, we will also report that such mutations perturbed phosphorylation status of MEK, thereby rendering MEK mutants constitutively active. Thus, dysregulation of post-translational modifications (such as phosphorylation and sumoylation) of the MEK MAPKK contributes to carcinogenesis.