Regulation of nuclear-cytoplasmic shuttling and function of Family with sequence similarity 13, member A (Fam13a), by B56-containing PP2As and Akt

Zhigang Jin; Jin Wei Chung; Wenyan Mei; Stefan Strack; Chunyan He; Gee W Lau; Jing Yang

doi:10.1091/mbc.E14-08-1276

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Regulation of nuclear-cytoplasmic shuttling and function of Family with sequence similarity 13, member A (Fam13a), by B56-containing PP2As and Akt

Journal article

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Peer reviewed

Regulation of nuclear-cytoplasmic shuttling and function of Family with sequence similarity 13, member A (Fam13a), by B56-containing PP2As and Akt

Zhigang Jin, Jin Wei Chung, Wenyan Mei, Stefan Strack, Chunyan He, Gee W Lau and Jing Yang

Molecular biology of the cell, Vol.26(6), pp.1160-1173

03/15/2015

DOI: 10.1091/mbc.E14-08-1276

PMCID: PMC4357514

PMID: 25609086

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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.

NIH 3T3 Cells

Lung Diseases - metabolism

Humans

Mice, Inbred C57BL

Xenopus laevis

Cytoplasm - metabolism

Male

Adipokines - metabolism

Nuclear Localization Signals

Mice, Knockout

14-3-3 Proteins - metabolism

Animals

Cell Nucleus - metabolism

Protein Isoforms - metabolism

HEK293 Cells

Protein Phosphatase 2 - metabolism

Protein Binding

Female

Mice

Protein Processing, Post-Translational

Active Transport, Cell Nucleus

Proto-Oncogene Proteins c-akt - metabolism

Wnt Signaling Pathway

Details

Title: Subtitle: Regulation of nuclear-cytoplasmic shuttling and function of Family with sequence similarity 13, member A (Fam13a), by B56-containing PP2As and Akt
Creators: Zhigang Jin - Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61802
Jin Wei Chung - Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61802
Wenyan Mei - Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61802
Stefan Strack - Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242
Chunyan He - Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN 46202
Gee W Lau - Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61802
Jing Yang - Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61802 yangj@illinois.edu
Resource Type: Journal article
Publication Details: Molecular biology of the cell, Vol.26(6), pp.1160-1173
DOI: 10.1091/mbc.E14-08-1276
PMID: 25609086
PMCID: PMC4357514
NLM abbreviation: Mol Biol Cell
ISSN: 1059-1524
eISSN: 1939-4586
Publisher: American Society for Cell Biology; United States
Grant note: R01 GM093217 / NIGMS NIH HHS R56 NS056244 / NINDS NIH HHS R01 NS043254 / NINDS NIH HHS R01GM093217 / NIGMS NIH HHS HL090699 / NHLBI NIH HHS R01NS043254 / NINDS NIH HHS R01 HL090699 / NHLBI NIH HHS R01 NS056244 / NINDS NIH HHS NS056244 / NINDS NIH HHS
Language: English
Date published: 03/15/2015
Academic Unit: Pathology; Iowa Neuroscience Institute; Neuroscience and Pharmacology
Record Identifier: 9984040575902771

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