title: Activated α2-Macroglobulin Regulates Transcriptional Activation of c-MYC Target Genes through Cell Surface GRP78 Protein.
abstract: Activated α2-macroglobulin (α2M*) signals predominantly through cell surface GRP78 (CS-GRP78) to promote proliferation and survival of cancer cells; however, the molecular mechanism remains obscure. c-MYC is an essential transcriptional regulator that controls cell proliferation. We hypothesize that α2M*/CS-GRP78-evoked key signaling events are required for transcriptional activation of c-MYC target genes. Activation of CS-GRP78 by α2M* requires ligation of the GRP78 primary amino acid sequence (Leu(98)-Leu(115)). After stimulation with α2M*, CS-GRP78 signaling activates 3-phosphoinositide-dependent protein kinase-1 (PDK1) to induce phosphorylation of PLK1, which in turn induces c-MYC transcription. We demonstrate that PLK1 binds directly to c-MYC and promotes its transcriptional activity by phosphorylating Ser(62) Moreover, activated c-MYC is recruited to the E-boxes of target genes FOSL1 and ID2 by phosphorylating histone H3 at Ser(10) In addition, targeting the carboxyl-terminal domain of CS-GRP78 with a mAb suppresses transcriptional activation of c-MYC target genes and impairs cell proliferation. This work demonstrates that α2M*/CS-GRP78 acts as an upstream regulator of the PDK1/PLK1 signaling axis to modulate c-MYC transcription and its target genes, suggesting a therapeutic strategy for targeting c-MYC-associated malignant progression.
authors.affiliation: From the Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Udhayakumar
authors.initials: U
authors.lastname: Gopal
authors.affiliation: From the Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Mario
authors.initials: M
authors.lastname: Gonzalez-Gronow
authors.affiliation: From the Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710 salvatore.pizzo@duke.edu.
authors.forename: Salvatore Vincent
authors.initials: SV
authors.lastname: Pizzo
mesh_terms: D045744:Cell Line, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051797:Inhibitor of Differentiation Protein 2 / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction; D015533:Transcriptional Activation; D000511:alpha-Macroglobulins / Q000235:genetics / Q000378:metabolism*; D000099169:Fos-Related Antigen 1
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D051797:Inhibitor of Differentiation Protein 2; D017346:Protein Serine-Threonine Kinases; D016760:Proto-Oncogene Proteins c-fos; D016271:Proto-Oncogene Proteins c-myc; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D000511:alpha-Macroglobulins; D000099169:Fos-Related Antigen 1; C000717247:HSPA5 protein, human; C497450:ID2 protein, human; C489427:MYC protein, human; C000631429:PDK1 protein, human
keywords: GRP78; MYC (c-MYC); PDK1; PLK1; tumor cell biology; tumor immunology; tumor therapy