title: Regulation of nuclear-cytoplasmic shuttling and function of Family with sequence similarity 13, member A (Fam13a), by B56-containing PP2As and Akt.
abstract: Recent genome-wide association studies reveal that the FAM13A gene is associated with human lung function and a variety of lung diseases, including chronic obstructive pulmonary disease, asthma, lung cancer, and pulmonary fibrosis. The biological functions of Fam13a, however, have not been studied. In an effort to identify novel substrates of B56-containing PP2As, we found that B56-containing PP2As and Akt act antagonistically to control reversible phosphorylation of Fam13a on Ser-322. We show that Ser-322 phosphorylation acts as a molecular switch to control the subcellular distribution of Fam13a. Fam13a shuttles between the nucleus and cytoplasm. When Ser-322 is phosphorylated by Akt, the binding between Fam13a and 14-3-3 is enhanced, leading to cytoplasmic sequestration of Fam13a. B56-containing PP2As dephosphorylate phospho-Ser-322 and promote nuclear localization of Fam13a. We generated Fam13a-knockout mice. Fam13a-mutant mice are viable and healthy, indicating that Fam13a is dispensable for embryonic development and physiological functions in adult animals. Intriguingly, Fam13a has the ability to activate the Wnt pathway. Although Wnt signaling remains largely normal in Fam13a-knockout lungs, depletion of Fam13a in human lung cancer cells causes an obvious reduction in Wnt signaling activity. Our work provides important clues to elucidating the mechanism by which Fam13a may contribute to human lung diseases.
authors.affiliation: Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61802.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Jin
authors.affiliation: Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61802.
authors.forename: Jin Wei
authors.initials: JW
authors.lastname: Chung
authors.affiliation: Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61802.
authors.forename: Wenyan
authors.initials: W
authors.lastname: Mei
authors.affiliation: Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242.
authors.forename: Stefan
authors.initials: S
authors.lastname: Strack
authors.affiliation: Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN 46202.
authors.forename: Chunyan
authors.initials: C
authors.lastname: He
authors.affiliation: Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61802.
authors.forename: Gee W
authors.initials: GW
authors.lastname: Lau
authors.affiliation: Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61802 yangj@illinois.edu.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D021581:Active Transport, Cell Nucleus; D054392:Adipokines / Q000378:metabolism*; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008171:Lung Diseases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D019913:Nuclear Localization Signals; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D014982:Xenopus laevis
chemical_list: D048948:14-3-3 Proteins; D054392:Adipokines; C584654:C1QTNF12 protein, human; D019913:Nuclear Localization Signals; D020033:Protein Isoforms; D051057:Proto-Oncogene Proteins c-akt; D054648:Protein Phosphatase 2