Browsing by keyword "ERK"

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    • The ERK MAPK Pathway Is Essential for Skeletal Development and Homeostasis
      Kim, Jung-Min; Yang, Yeon-Suk; Park, Kwang Hwan; Oh, Hwanhee; Greenblatt, Matthew B.; Shim, Jae-Hyuck (2019-04-12)
      Mitogen-activated protein kinases (MAPKs) are a family of protein kinases that function as key signal transducers of a wide spectrum of extracellular stimuli, including growth factors and pro-inflammatory cytokines. Dysregulation of the extracellular signal-regulated kinase (ERK) MAPK pathway is associated with human skeletal abnormalities including Noonan syndrome, neurofibromatosis type 1, and cardiofaciocutaneous syndrome. Here, we demonstrate that ERK activation in osteoprogenitors is required for bone formation during skeletal development and homeostasis. Deletion of Mek1 and Mek2, kinases upstream of ERK MAPK, in osteoprogenitors (Mek1(Osx)Mek2(-/-)), resulted in severe osteopenia and cleidocranial dysplasia (CCD), similar to that seen in humans and mice with impaired RUNX2 function. Additionally, tamoxifen-induced deletion of Mek1 and Mek2 in osteoprogenitors in adult mice (Mek1(Osx-ERT)Mek2(-/-)) significantly reduced bone mass. Mechanistically, this corresponded to decreased activation of osteoblast master regulators, including RUNX2, ATF4, and beta-catenin. Finally, we identified potential regulators of osteoblast differentiation in the ERK MAPK pathway using unbiased phospho-mass spectrometry. These observations demonstrate essential roles of ERK activation in osteogenesis and bone formation.

    • TNF and MAP kinase signalling pathways
      Sabio, Guadalupe; Davis, Roger J. (2014-06-01)
      The binding of tumour necrosis factor alpha (TNFalpha) to cell surface receptors engages multiple signal transduction pathways, including three groups of mitogen-activated protein (MAP) kinases: extracellular-signal-regulated kinases (ERKs); the cJun NH2-terminal kinases (JNKs); and the p38 MAP kinases. These MAP kinase signalling pathways induce a secondary response by increasing the expression of several inflammatory cytokines (including TNFalpha) that contribute to the biological activity of TNFalpha. MAP kinases therefore function both upstream and down-stream of signalling by TNFalpha receptors. Here we review mechanisms that mediate these actions of MAP kinases during the response to TNFalpha.