title: Fyn-phosphorylated PIKE-A binds and inhibits AMPK signaling, blocking its tumor suppressive activity.
abstract: The AMP-activated protein kinase, a key regulator of energy homeostasis, has a critical role in metabolic disorders and cancers. AMPK is mainly regulated by cellular AMP and phosphorylation by upstream kinases. Here, we show that PIKE-A binds to AMPK and blocks its tumor suppressive actions, which are mediated by tyrosine kinase Fyn. PIKE-A directly interacts with AMPK catalytic alpha subunit and impairs T172 phosphorylation, leading to repression of its kinase activity on the downstream targets. Mutation of Fyn phosphorylation sites on PIKE-A, depletion of Fyn, or pharmacological inhibition of Fyn blunts the association between PIKE-A and AMPK, resulting in loss of its inhibitory effect on AMPK. Cell proliferation and oncogenic assays demonstrate that PIKE-A antagonizes tumor suppressive actions of AMPK. In human glioblastoma samples, PIKE-A expression inversely correlates with the p-AMPK levels, supporting that PIKE-A negatively regulates AMPK activity in cancers. Thus, our findings provide additional layer of molecular regulation of the AMPK signaling pathway in cancer progression.
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, 30322 GA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, 30322 GA, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Qi
authors.affiliation: Department of Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, 73104 OK, USA.
authors.forename: C B
authors.identifier: http://orcid.org/0000-0002-2787-9575
authors.initials: CB
authors.lastname: Chan
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, 30322 GA, USA.|Winship Cancer Institute, Emory University School of Medicine, Atlanta, 30322 GA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, 30322 GA, USA.|Winship Cancer Institute, Emory University School of Medicine, Atlanta, 30322 GA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Pathology and Lab Medicine, Harvard Medical School and Children's Hospital, Boston, 02115 MA, USA.
authors.forename: H R
authors.initials: HR
authors.lastname: Luo
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, 30322 GA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Appin
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, 30322 GA, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Brat
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, 30322 GA, USA.|Winship Cancer Institute, Emory University School of Medicine, Atlanta, 30322 GA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Ye
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D020690:GTPase-Activating Proteins; D025521:Tumor Suppressor Proteins; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; C485997:AGAP2 protein, human; D019204:GTP-Binding Proteins