title: Fas-associated phosphatase 1 (Fap1) influences βcatenin activity in myeloid progenitor cells expressing the Bcr-abl oncogene.
abstract: Increased βcatenin activity correlates with leukemia stem cell expansion and disease progression in chronic myeloid leukemia (CML). We found previously that expression of the CML-related Bcr-abl oncoprotein in myeloid progenitor cells increases expression of Fas-associated phosphatase 1 (Fap1). This resulted in Fap1-dependent resistance to Fas-induced apoptosis in these cells. Fap1 also interacts with the adenomatous polyposis coli (Apc) protein, but the functional significance of this interaction is unknown. Apc participates in a complex that includes glycogen synthase kinase β (Gsk3β) and βcatenin. Assembly of this complex results in phosphorylation of βcatenin by Gsk3β, which facilitates βcatenin ubiquitination and degradation by the proteasome. In this study, we found increased association of Fap1 with the Apc complex in Bcr-abl(+) myeloid progenitor cells. We also found Fap1-dependent inactivation of Gsk3β and consequent stabilization of βcatenin in these cells. Consistent with this, Bcr-abl(+) cells exhibited a Fap1-dependent increase in βcatenin activity. Our studies identified Fap1-dependent Gsk3β inactivation as a molecular mechanism for increased βcatenin activity in CML.
authors.affiliation: Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois, USA.
authors.forename: Weiqi
authors.initials: W
authors.lastname: Huang
authors.forename: Ling
authors.initials: L
authors.lastname: Bei
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Eklund
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis* / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D023461:Myeloid Progenitor Cells / Q000201:enzymology* / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation / Q000235:genetics; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13 / Q000235:genetics / Q000378:metabolism*; D020298:U937 Cells; D054875:Ubiquitination / Q000235:genetics; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D046912:Multiprotein Complexes; D051176:beta Catenin; D016044:Fusion Proteins, bcr-abl; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C516742:PTPN13 protein, human; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13
keywords: Fas; Gene Regulation; Glycogen Synthase Kinase 3; Leukemia; βcatenin