title: Tetraspanin CD82 Regulates the Spatiotemporal Dynamics of PKCα in Acute Myeloid Leukemia.
abstract: Patients with acute myeloid leukemia (AML) have increased myeloid cells within their bone marrow that exhibit aberrant signaling. Therefore, therapeutic targets that modulate disrupted signaling cascades are of significant interest. In this study, we demonstrate that the tetraspanin membrane scaffold, CD82, regulates protein kinase c alpha (PKCα)-mediated signaling critical for AML progression. Utilizing a palmitoylation mutant form of CD82 with disrupted membrane organization, we find that the CD82 scaffold controls PKCα expression and activation. Combining single molecule and ensemble imaging measurements, we determine that CD82 stabilizes PKCα activation at the membrane and regulates the size of PKCα membrane clusters. Further evaluation of downstream effector signaling identified robust and sustained activation of ERK1/2 upon CD82 overexpression that results in enhanced AML colony formation. Together, these data propose a mechanism where CD82 membrane organization regulates sustained PKCα signaling that results in an aggressive leukemia phenotype. These observations suggest that the CD82 scaffold may be a potential therapeutic target for attenuating aberrant signal transduction in AML.
authors.affiliation: Department of Pathology, University of New Mexico Health Sciences Center, University of New Mexico, MSC 08-4640, Albuquerque, NM 87131, USA.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Termini
authors.affiliation: Department of Physics and Astronomy, University of New Mexico, MSC 07-4220, Albuquerque, NM 87131, USA.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Lidke
authors.affiliation: Department of Pathology, University of New Mexico Health Sciences Center, University of New Mexico, MSC 08-4640, Albuquerque, NM 87131, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Gillette
mesh_terms: D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D018450:Disease Progression; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics; D006801:Humans; D051861:Kangai-1 Protein / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D054878:Lipoylation; D051571:Protein Kinase C-alpha / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D059470:Tetraspanins / Q000235:genetics* / Q000378:metabolism
chemical_list: C497688:CD82 protein, human; D051861:Kangai-1 Protein; D059470:Tetraspanins; C496628:PRKCA protein, human; D051571:Protein Kinase C-alpha