Ligation of cell surface GRP78 with antibody directed against the COOH-terminal domain of GRP78 suppresses Ras/MAPK and PI 3-kinase/AKT signaling while promoting caspase activation in human prostate cancer cells.
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We have previously shown that treatment of prostate cancer and melanoma cells expressing GRP78 on their cell surface with antibody directed against the COOH-terminal domain of GRP78 upregulates and activates p53 causing decreased cell proliferation and upregulated apoptosis. In this report, we demonstrate that treatment of 1-LN prostate cancer cells with this antibody decreases cell surface expression of GRP78, Akt(Thr308) and Akt(Ser473) kinase activities and reduces phosphorylation of FOXO, and GSK3beta. This treatment also suppresses activation of ERK1/2, p38 MAPK and MKK3/6; however, it upregulates MKK4 activity. JNK, as determined by its phosphorylation state, is subsequently activated, triggering apoptosis. Incubation of cells with antibody reduced levels of anti-apoptotic Bcl-2, while elevating pro-apoptotic BAD, BAX and BAK expression as well as cleaved caspases-3, -7, -8 and -9. Silencing GRP78 or p53 gene expression by RNAi prior to antibody treatment abrogated these effects. We conclude that antibody directed against the COOH-terminal domain of GRP78 may prove useful as a pan suppressor of proliferative/survival signaling in cancer cells expressing GRP78 on their cell surface.
Amino Acid Sequence
Cell Line, Tumor
Gene Knockdown Techniques
MAP Kinase Signaling System
Mitogen-Activated Protein Kinases
Molecular Sequence Data
Protein Structure, Tertiary
Proto-Oncogene Proteins c-akt
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Professor Emeritus of Pathology
1. Biology of α2MSR: Ligands binding and their regulation, receptor upregulation, defining signaling cascades components, modulation of ser/thr/tyr kinase activities, cellular responses (mitogenesis, gene expression), physiological relevance. 2. Receptor activation, and membrane phospholipases - PLA2, PI-PLCb, PI-PLCg, PC-PLC, PLD, sphingomyelinase, and ceramide signaling, regulation, role in mitogenesis. 3. α2MSR and malignancy - Pro
Distinguished Professor of Pathology, in the School of Medicine
RESEARCH ABSTRACT Studies from this laboratory identified cell surface expression of the molecular chaperone GRP78 as a major factor in prostate cancer and other malignancies. Cell surface GRP78 functions as a signaling receptor promoting tumor proliferation and suppressing apoptosis. Patients with a number of malignancies mount an autoimmune response to GRP78 and these antibodies, which bind to the NH2 terminal domains of GRP78, are receptor agonists whose appearanc
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Daaka, Y; Pitcher, JA; Richardson, M; Stoffel, RH; Robishaw, JD; Lefkowitz, RJ (Proc Natl Acad Sci U S A, 1997-03-18)The G protein-coupled receptor (GPCR) kinases (GRKs) phosphorylate and desensitize agonist-occupied GPCRs. GRK2-mediated receptor phosphorylation is preceded by the agonist-dependent membrane association of this enzyme. ...
Hybrid transgenic mice reveal in vivo specificity of G protein-coupled receptor kinases in the heart. Eckhart, AD; Duncan, SJ; Penn, RB; Benovic, JL; Lefkowitz, RJ; Koch, WJ (Circ Res, 2000-01-07)G protein-coupled receptor kinases (GRKs) phosphorylate activated G protein-coupled receptors, including alpha(1B)-adrenergic receptors (ARs), resulting in desensitization. In vivo analysis of GRK substrate selectivity has ...
Oppermann, M; Diversé-Pierluissi, M; Drazner, MH; Dyer, SL; Freedman, NJ; Peppel, KC; Lefkowitz, RJ (Proc Natl Acad Sci U S A, 1996-07-23)Guanine nucleotide-binding regulatory protein (G protein)-coupled receptor kinases (GRKs) constitute a family of serine/threonine kinases that play a major role in the agonist-induced phosphorylation and desensitization ...