A Single Kinase Generates the Majority of the Secreted Phosphoproteome

Cell, Год журнала: 2015, Номер 161(7), С. 1619 - 1632

Опубликована: Июнь 1, 2015

Язык: Английский

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Dynamic regulation of FGF23 by Fam20C phosphorylation, GalNAc-T3 glycosylation, and furin proteolysis

Proceedings of the National Academy of Sciences, Год журнала: 2014, Номер 111(15), С. 5520 - 5525

Опубликована: Март 26, 2014

The family with sequence similarity 20, member C (Fam20C) has recently been identified as the Golgi casein kinase. Fam20C phosphorylates secreted proteins on Ser-x-Glu/pSer motifs and loss-of-function mutations in kinase cause Raine syndrome, an often-fatal osteosclerotic bone dysplasia. is potentially upstream regulator of phosphate-regulating hormone fibroblast growth factor 23 (FGF23), because humans FAM20C KO mice develop hypophosphatemia due to increase full-length, biologically active FGF23. However, mechanism by which regulates FGF23 unknown. Here we show that directly Ser(180), within R(176)XXR(179)/S(180)AE subtilisin-like proprotein convertase motif. This phosphorylation event inhibits O-glycosylation polypeptide N-acetylgalactosaminyltransferase 3 (GalNAc-T3), promotes cleavage inactivation furin. Collectively, our results provide a molecular dynamically regulated phosphorylation, glycosylation, proteolysis. Furthermore, findings suggest cross-talk between secretory pathway may be important are regulated.

Язык: Английский

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The kinome 'at large' in cancer

Nature reviews. Cancer, Год журнала: 2016, Номер 16(2), С. 83 - 98

Опубликована: Янв. 29, 2016

Язык: Английский

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The sequence at Spike S1/S2 site enables cleavage by furin and phospho-regulation in SARS-CoV2 but not in SARS-CoV1 or MERS-CoV

Scientific Reports, Год журнала: 2020, Номер 10(1)

Опубликована: Окт. 9, 2020

Abstract The Spike protein of the novel coronavirus SARS-CoV2 contains an insertion 680 S PRRA R↓SV 687 forming a cleavage motif RxxR for furin-like enzymes at boundary S1/S2 subunits. Cleavage is important efficient viral entry into target cells. absent in other CoV-s same clade, including SARS-CoV1 that caused 2003 outbreak. However, analogous was present more distant Middle East Respiratory Syndrome MERS-CoV. We show crucial third arginine left middle position, comprising R xR required furin recognition vitro, while general common with MERS-CoV not sufficient cleavage. Further, we describe surprising finding two serines edges insert PRRAR↓ V can be efficiently phosphorylated by proline-directed and basophilic kinases. Both phosphorylations switch off furin’s ability to cleave site. Although phospho-regulation secreted proteins still poorly understood, further studies, supported recent report ten vivo sites SARS-CoV2, could potentially uncover regulatory mechanisms SARS-CoV2.

Язык: Английский

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Casein kinase: the triple meaning of a misnomer

Biochemical Journal, Год журнала: 2014, Номер 460(2), С. 141 - 156

Опубликована: Май 13, 2014

The term ‘casein kinase’ has been widely used for decades to denote protein kinases sharing the ability readily phosphorylate casein in vitro. These fall into three main classes: two of them, later renamed as CK1 (casein kinase 1, also known CKI) and CK2 (also CKII), are pleiotropic members kinome functionally unrelated casein, whereas G-CK, or genuine kinase, responsible phosphorylation Golgi apparatus lactating mammary gland, only identified recently with Fam20C [family sequence similarity 20C; DMP-4 (dentin matrix protein-4)], a member four-jointed family atypical kinases, being many secreted proteins. In hindsight, therefore, is misleading every instance; case CK2, it because not physiological substrate, G-CK/Fam20C/DMP-4, just one out plethora its targets, rather marginal at that. Strikingly, altogether, albeit representing minimal proportion whole kinome, appear be generation up 40–50% non-redundant phosphosites currently retrieved human phosphopeptides database. present review, short historical explanation will provided accounting usage same misnomer classes together an update our current knowledge these enzymes, while playing very distinct biological roles.

Язык: Английский

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A Secreted Tyrosine Kinase Acts in the Extracellular Environment

Cell, Год журнала: 2014, Номер 158(5), С. 1033 - 1044

Опубликована: Авг. 1, 2014

Язык: Английский

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A secretory kinase complex regulates extracellular protein phosphorylation

eLife, Год журнала: 2015, Номер 4

Опубликована: Март 19, 2015

Although numerous extracellular phosphoproteins have been identified, the protein kinases within secretory pathway only recently discovered, and their regulation is virtually unexplored. Fam20C physiological Golgi casein kinase, which phosphorylates many secreted proteins critical for proper biomineralization. Fam20A, a paralog, essential enamel formation, but biochemical function of Fam20A unknown. Here we show that potentiates kinase activity promotes phosphorylation matrix in vitro cells. Mechanistically, pseudokinase forms functional complex with Fam20C, this enhances pathway. Our findings shed light on molecular mechanism by collaborate to control provide first insight into phosphorylation.

Язык: Английский

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Xylose phosphorylation functions as a molecular switch to regulate proteoglycan biosynthesis

Proceedings of the National Academy of Sciences, Год журнала: 2014, Номер 111(44), С. 15723 - 15728

Опубликована: Окт. 20, 2014

Significance Proteoglycans are cellular proteins modified with long chains of repeating sugar residues connected to serine within the protein core by a short tetrasaccharide linker. perform critical functions such as formation extracellular matrix, binding diverse array molecules, and regulation cell motility, adhesion, cell–cell communication. We show here that family sequence similarity 20, member B (Fam20B) is xylose kinase phosphorylates residue proteoglycan linkage. Xylose phosphorylation dramatically stimulates activity galactosyltransferase II (GalT-II, B3GalT6), an enzyme adds galactose growing Cells lacking Fam20B cannot extend linkage thus have immature nonfunctional proteoglycan, phenotype remarkably similar Ehlers-Danlos syndrome caused inactivating GalT-II mutations.

Язык: Английский

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Phosphorylation switches protein disulfide isomerase activity to maintain proteostasis and attenuate ER stress

The EMBO Journal, Год журнала: 2020, Номер 39(10)

Опубликована: Март 9, 2020

Язык: Английский

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High-throughput screening of mouse gene knockouts identifies established and novel skeletal phenotypes

Bone Research, Год журнала: 2014, Номер 2(1)

Опубликована: Окт. 28, 2014

Screening gene function in vivo is a powerful approach to discover novel drug targets. We present high-throughput screening (HTS) data for 3 762 distinct global knockout (KO) mouse lines with viable adult homozygous mice generated using either gene-trap or homologous recombination technologies. Bone mass was determined from DEXA scans of male and female at 14 weeks age by microCT analyses bones 16 age. Wild-type (WT) cagemates/littermates were examined each KO. Lethality observed an additional 850 KO lines. Since primary HTS are susceptible false positive findings, cohorts intriguing bone examined. Aging, ovariectomy, histomorphometry strength studies performed possible non-skeletal phenotypes explored. Together, these screens identified multiple genes affecting mass: 23 previously reported (Calcr, Cebpb, Crtap, Dcstamp, Dkk1, Duoxa2, Enpp1, Fgf23, Kiss1/Kiss1r, Kl (Klotho), Lrp5, Mstn, Neo1, Npr2, Ostm1, Postn, Sfrp4, Slc30a5, Slc39a13, Sost, Sumf1, Src, Wnt10b), five extensively characterized (Cldn18, Fam20c, Lrrk1, Sgpl1, Wnt16), preliminary characterization (Agpat2, Rassf5, Slc10a7, Slc26a7, Slc30a10) three undisclosed coding potential osteoporosis

Язык: Английский

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