Activation of Raf-mitogen-activated protein kinase signaling pathway by 1,25-dihydroxyvitamin D3 in normal human keratinocytes.
The biologic effects of the vitamin D hormone 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) are believed to be mediated by an intracellular vitamin D receptor, which after ligand binding acts as a transcription factor modulating expression of a variety of genes. Besides having a well-known role in calcium metabolism, this hormone is an important regulator of proliferation in a majority of normal and neoplastic cells. Keratinocytes provide a convenient model for investigating the growth-related effects of vitamin D in normal cells. Growth of keratinocytes may be either stimulated or inhibited by 1,25(OH)2D3, depending on the degree of cell differentiation. We show here that 1,25(OH)2D3 stimulates DNA synthesis via sequential activation of Raf and the mitogen-activated protein kinase. Activation of these kinases is independent on protein and mRNA synthesis and is preceded by rapid tyrosine phosphorylation of an adaptor protein p66 (Shc) and formation of a complex between p66 Shc, a bridging molecule Grb2, and a Ras activator, mSos. Vitamin D receptor protein associates with Shc, indicating that this steroid hormone is able to signal through the transcription-independent pathways similar to those used by peptide hormones and cytokines.
Gniadecki
R
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Department of Dermatological Research, Leo Pharmaceutical Products, Ballerup, Denmark.
D048868:Adaptor Proteins, Signal Transducing; D002117:Calcitriol / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D051380:GRB2 Adaptor Protein; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf; D012016:Reference Values; D015398:Signal Transduction / Q000187:drug effects*; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D011506:Proteins; D011518:Proto-Oncogene Proteins; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D002117:Calcitriol