A Single Kinase Generates the Majority of the Secreted Phosphoproteome.

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Tagliabracci VS, Wiley SE, Guo X, Kinch LN, Durrant E, Wen J, Xiao J, Cui J, Nguyen KB, Engel JL, Coon JJ, Grishin N, Pinna LA, Pagliarini DJ, Dixon JE

A Single Kinase Generates the Majority of the Secreted Phosphoproteome.

Cell. 2015 Jun 18;161(7):1619-32. doi: 10.1016/j.cell.2015.05.028.

PubMed ID
26091039 [ View in PubMed
]
Abstract

The existence of extracellular phosphoproteins has been acknowledged for over a century. However, research in this area has been undeveloped largely because the kinases that phosphorylate secreted proteins have escaped identification. Fam20C is a kinase that phosphorylates S-x-E/pS motifs on proteins in milk and in the extracellular matrix of bones and teeth. Here, we show that Fam20C generates the majority of the extracellular phosphoproteome. Using CRISPR/Cas9 genome editing, mass spectrometry, and biochemistry, we identify more than 100 secreted phosphoproteins as genuine Fam20C substrates. Further, we show that Fam20C exhibits broader substrate specificity than previously appreciated. Functional annotations of Fam20C substrates suggest roles for the kinase beyond biomineralization, including lipid homeostasis, wound healing, and cell migration and adhesion. Our results establish Fam20C as the major secretory pathway protein kinase and serve as a foundation for new areas of investigation into the role of secreted protein phosphorylation in human biology and disease.

DrugBank Data that Cites this Article

Polypeptides
NameUniProt ID
Coagulation factor VP12259Details
Antithrombin-IIIP01008Details
Vitamin K-dependent protein CP04070Details
SerotransferrinP02787Details
Serum albuminP02768Details
Fibrinogen alpha chainP02671Details
Heparin cofactor 2P05546Details
Interleukin-6P05231Details
Apolipoprotein A-IIP02652Details
Alpha-1-antitrypsinP01009Details
Insulin-like growth factor-binding protein 3P17936Details
Kininogen-1P01042Details
Apolipoprotein EP02649Details
CeruloplasminP00450Details
EndoplasminP14625Details
FibronectinP02751Details
Fibrinogen gamma chainP02679Details
Laminin subunit beta-1P07942Details
Laminin subunit gamma-1P11047Details
Syndecan-2P34741Details
Insulin-like growth factor-binding protein 7Q16270Details
Disintegrin and metalloproteinase domain-containing protein 10O14672Details
Protein disulfide-isomeraseP07237Details
Amyloid beta A4 proteinP05067Details
Complement C3P01024Details
MesothelinQ13421Details
Galectin-1P09382Details
Versican core proteinP13611Details
Complement C4-AP0C0L4Details
Proprotein convertase subtilisin/kexin type 9Q8NBP7Details
Nucleobindin-1Q02818Details
Bone morphogenetic protein 4P12644Details
Alpha-2-HS-glycoproteinP02765Details
Inter-alpha-trypsin inhibitor heavy chain H2P19823Details
Apolipoprotein L1O14791Details
Amyloid-like protein 2Q06481Details
Insulin-like growth factor-binding protein 1P08833Details
Insulin-like growth factor-binding protein 4P22692Details
Insulin-like growth factor-binding protein 5P24593Details
Apolipoprotein B-100P04114Details