Identification of FAM53C as a cytosolic-anchoring inhibitory binding protein of the kinase DYRK1A

Abu Jhaisha S, Widowati EW, Kii I, Sonamoto R, Knapp S, Papadopoulos C,

Becker W (2017) DYRK1B mutations associated with metabolic

syndrome impair the chaperone-dependent maturation of the kinase

domain. Sci Rep 7: 6420. doi:10.1038/s41598-017-06874-w

Altafaj X, Dierssen M, Baamonde C, Martı´ E, Visa J, Guimer a` J, Oset M,

Gonzalez

JR, Flórez J, Fillat C, et al (2001) Neurodevelopmental

delay, motor abnormalities and cognitive deficits in transgenic

mice overexpressing Dyrk1A (minibrain), a murine model of

Down’s syndrome. Hum Mol Genet 10: 1915–1923. doi:10.1093/hmg/

10.18.1915

Alvarez

M, Estivill X, de la Luna S (2003) DYRK1A accumulates in splicing

speckles through a novel targeting signal and induces speckle

disassembly. J Cell Sci 116: 3099–3107. doi:10.1242/jcs.00618

Alvarez M, Altafaj X, Aranda S, de la Luna S (2007) DYRK1A

autophosphorylation on serine residue 520 modulates its kinase

activity via 14-3-3 binding. Mol Biol Cell 18: 1167–1178. doi:10.1091/

mbc.e06-08-0668

Aranda S, Alvarez M, Turró S, Laguna A, de la Luna S (2008) Sprouty2mediated inhibition of fibroblast growth factor signaling is modulated

by the protein kinase DYRK1A. Mol Cell Biol 28: 5899–5911. doi:10.1128/

MCB.00394-08

Aranda S, Laguna A, de la Luna S (2011) DYRK family of protein kinases:

Evolutionary relationships, biochemical properties, and functional

roles. FASEB J 25: 449–462. doi:10.1096/fj.10-165837

Data Availability

Arbones ML, Thomazeau A, Nakano-Kobayashi A, Hagiwara M, Delabar JM

(2019) DYRK1A and cognition: A lifelong relationship. Pharmacol Ther

194: 199–221. doi:10.1016/j.pharmthera.2018.09.010

This study does not contain deposited data in external repositories.

Original data can be provided upon request.

Arron JR, Winslow MM, Polleri A, Chang CP, Wu H, Gao X, Neilson JR, Chen L,

Heit JJ, Kim SK, et al (2006) NFAT dysregulation by increased dosage of

FAM53C binds and inhibits DYRK1A in the cytoplasm

Miyata and Nishida

https://doi.org/10.26508/lsa.202302129

vol 6 | no 12 | e202302129

14 of 17

DSCR1 and DYRK1A on chromosome 21. Nature 441: 595–600.

doi:10.1038/nature04678

Atas-Ozcan H, Brault V, Duchon A, Herault Y (2021) Dyrk1a from gene function

in development and physiology to dosage correction across life span

in Down syndrome. Genes 12: 1833. doi:10.3390/genes12111833

Becker W, Joost H-G (1999) Structural and functional characteristics of DYRK,

a novel subfamily of protein kinases with dual specificity. Prog Nucleic

Acid Res Mol Biol 62: 1–17. doi:10.1016/s0079-6603(08)60503-6

Becker W, Sippl W (2011) Activation, regulation, and inhibition of DYRK1A. FEBS

J 278: 246–256. doi:10.1111/j.1742-4658.2010.07956.x

Becker W, Weber Y, Wetzel K, Eirmbter K, Tejedor FJ, Joost H-G (1998)

Sequence characteristics, subcellular localization, and substrate

specificity of DYRK-related kinases, a novel family of dual specificity

protein kinases. J Biol Chem 273: 25893–25902. doi:10.1074/

jbc.273.40.25893

Bhansali RS, Rammohan M, Lee P, Laurent AP, Wen Q, Suraneni P, Yip BH, Tsai

YC, Jenni S, Bornhauser B, et al (2021) DYRK1A regulates B cell acute

lymphoblastic leukemia through phosphorylation of FOXO1 and

STAT3. J Clin Invest 131: e135937. doi:10.1172/JCI135937

Blazek JD, Abeysekera I, Li J, Roper RJ (2015) Rescue of the abnormal skeletal

phenotype in Ts65Dn Down syndrome mice using genetic and

therapeutic modulation of trisomic Dyrk1a. Hum Mol Genet 24:

5687–5696. doi:10.1093/hmg/ddv284

Branca C, Shaw DM, Belfiore R, Gokhale V, Shaw AY, Foley C, Smith B, Hulme C,

Dunckley T, Meechoovet B, et al (2017) Dyrk1 inhibition improves

Alzheimer’s disease-like pathology. Aging Cell 16: 1146–1154.

doi:10.1111/acel.12648

Courcet JB, Faivre L, Malzac P, Masurel-Paulet A, Lopez E, Callier P, Lambert

L, Lemesle M, Thevenon J, Gigot N, et al (2012) The DYRK1A gene is a

cause of syndromic intellectual disability with severe microcephaly

and epilepsy. J Med Genet 49: 731–736. doi:10.1136/jmedgenet-2012101251

Glenewinkel F, Cohen MJ, King CR, Kaspar S, Bamberg-Lemper S, Mymryk JS,

Becker W (2016) The adaptor protein DCAF7 mediates the interaction

of the adenovirus E1A oncoprotein with the protein kinases DYRK1A

and HIPK2. Sci Rep 6: 28241. doi:10.1038/srep28241

Guard SE, Poss ZC, Ebmeier CC, Pagratis M, Simpson H, Taatjes DJ, Old WM

(2019) The nuclear interactome of DYRK1A reveals a functional role

in DNA damage repair. Sci Rep 9: 6539. doi:10.1038/s41598-01942990-5

Gwack Y, Sharma S, Nardone J, Tanasa B, Iuga A, Srikanth S, Okamura H,

Bolton D, Feske S, Hogan PG, et al (2006) A genome-wide Drosophila

RNAi screen identifies DYRK-family kinases as regulators of NFAT.

Nature 441: 646–650. doi:10.1038/nature04631

Ha¨ mmerle B, Elizalde C, Galceran J, Becker W, Tejedor FJ (2003) The Mnb/

Dyrk1A protein kinase: Neurobiological functions and Down syndrome

implications. Adv Down Syndr Res 67: 129–137. doi:10.1007/978-3-70916721-2_11

Himpel S, Tegge W, Frank R, Leder S, Joost HG, Becker W (2000) Specificity

determinants of substrate recognition by the protein kinase DYRK1A. J

Biol Chem 275: 2431–2438. doi:10.1074/jbc.275.4.2431

Himpel S, Panzer P, Eirmbter K, Czajkowska H, Sayed M, Packman LC, Blundell

T, Kentrup H, Grotzinger

J, Joost HG, et al (2001) Identification of the

autophosphorylation sites and characterization of their effects in the

protein kinase DYRK1A. Biochem J 359: 497–505. doi:10.1042/0264-6021:

3590497

Huttlin EL, Bruckner RJ, Paulo JA, Cannon JR, Ting L, Baltier K, Colby G, Gebreab

F, Gygi MP, Parzen H, et al (2017) Architecture of the human

interactome defines protein communities and disease networks.

Nature 545: 505–509. doi:10.1038/nature22366

Huttlin EL, Bruckner RJ, Navarrete-Perea J, Cannon JR, Baltier K, Gebreab F,

Gygi MP, Thornock A, Zarraga G, Tam S, et al (2021) Dual proteomescale networks reveal cell-specific remodeling of the human

interactome. Cell 184: 3022–3040.e28. doi:10.1016/j.cell.2021.04.011

Courraud J, Chater-Diehl E, Durand B, Vincent M, Del Mar Muniz Moreno M,

Boujelbene I, Drouot N, Genschik L, Schaefer E, Nizon M, et al (2021)

Integrative approach to interpret DYRK1A variants, leading to a

frequent neurodevelopmental disorder. Genet Med 23: 2150–2159.

doi:10.1038/s41436-021-01263-1

Kimura R, Kamino K, Yamamoto M, Nuripa A, Kida T, Kazui H, Hashimoto R,

Tanaka T, Kudo T, Yamagata H, et al (2007) The DYRK1A gene, encoded

in chromosome 21 Down syndrome critical region, bridges between

beta-amyloid production and tau phosphorylation in Alzheimer

disease. Hum Mol Genet 16: 15–23. doi:10.1093/hmg/ddl437

De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, Kou Y, Liu L,

Fromer M, Walker S, et al (2014) Synaptic, transcriptional and

chromatin genes disrupted in autism. Nature 515: 209–215.

doi:10.1038/nature13772

Koyasu S, Nishida E, Kadowaki T, Matsuzaki F, Iida K, Harada F, Kasuga M, Sakai

H, Yahara I (1986) Two mammalian heat shock proteins, HSP90 and

HSP100, are actin-binding proteins. Proc Natl Acad Sci U S A 83:

8054–8058. doi:10.1073/pnas.83.21.8054

Di Vona C, Bezdan D, Islam AB, Salichs E, López-Bigas N, Ossowski S, de la

Luna S (2015) Chromatin-wide profiling of DYRK1A reveals a role as a

gene-specific RNA polymerase II CTD kinase. Mol Cell 57: 506–520.

doi:10.1016/j.molcel.2014.12.026

Kumar K, Suebsuwong C, Wang P, Garcia-Ocaña A, Stewart AF, DeVita RJ (2021)

DYRK1A inhibitors as potential therapeutics for beta-cell regeneration

for diabetes. J Med Chem 64: 2901–2922. doi:10.1021/

acs.jmedchem.0c02050

Duchon A, Herault

Y (2016) DYRK1A, a dosage-sensitive gene involved in

neurodevelopmental disorders, is a target for drug development in

Down syndrome. Front Behav Neurosci 10: 104. doi:10.3389/

fnbeh.2016.00104

Li D, Jackson RA, Yusoff P, Guy GR (2010) Direct association of sprouty-related

protein with an EVH1 domain (SPRED) 1 or SPRED2 with DYRK1A

modifies substrate/kinase interactions. J Biol Chem 285: 35374–35385.

doi:10.1074/jbc.M110.148445

Feki A, Hibaoui Y (2018) DYRK1A protein, A promising therapeutic target to

improve cognitive deficits in Down syndrome. Brain Sci 8: 187.

doi:10.3390/brainsci8100187

Li S, Xu C, Fu Y, Lei PJ, Yao Y, Yang W, Zhang Y, Washburn MP, Florens L, Jaiswal

M, et al (2018) DYRK1A interacts with histone acetyl transferase p300

and CBP and localizes to enhancers. Nucleic Acids Res 46: 11202–11213.

doi:10.1093/nar/gky754

´ M, Mart´ı E, Avila J, Dierssen

Ferrer I, Barrachina M, Puig B, Mart´ınez de Lagran

M (2005) Constitutive Dyrk1A is abnormally expressed in Alzheimer

disease, Down syndrome, Pick disease, and related transgenic

models. Neurobiol Dis 20: 392–400. doi:10.1016/j.nbd.2005.03.020

Frendo-Cumbo S, Li T, Ammendolia DA, Coyaud E, Laurent EMN, Liu Y, Bilan PJ,

Polevoy G, Raught B, Brill JA, et al (2022) DCAF7 regulates cell

proliferation through IRS1-FOXO1 signaling. iScience 25: 105188.

doi:10.1016/j.isci.2022.105188

Galceran J, Graaf K, Tejedor FJ, Becker W (2003) The Mnb/Dyrk1A protein

kinase: Genetic and biochemical properties. Adv Down Syndr Res 67:

139–148. doi:10.1007/978-3-7091-6721-2_12

FAM53C binds and inhibits DYRK1A in the cytoplasm

Miyata and Nishida

Lochhead PA, Sibbet G, Morrice N, Cleghon V (2005) Activation-loop

autophosphorylation is mediated by a novel transitional

intermediate form of DYRKs. Cell 121: 925–936. doi:10.1016/

j.cell.2005.03.034

Lu H, Yu D, Hansen AS, Ganguly S, Liu R, Heckert A, Darzacq X, Zhou Q (2018)

Phase-separation mechanism for C-terminal hyperphosphorylation

of RNA polymerase II. Nature 558: 318–323. doi:10.1038/s41586-0180174-3

Mart´ı E, Altafaj X, Dierssen M, de la Luna S, Fotaki V, Alvarez M, Perez-Riba

M,

Ferrer I, Estivill X (2003) Dyrk1A expression pattern supports specific

https://doi.org/10.26508/lsa.202302129

vol 6 | no 12 | e202302129

15 of 17

roles of this kinase in the adult central nervous system. Brain Res 964:

250–263. doi:10.1016/s0006-8993(02)04069-6

Mazmanian G, Kovshilovsky M, Yen D, Mohanty A, Mohanty S, Nee A, Nissen RM

(2010) The zebrafish dyrk1b gene is important for endoderm

formation. Genesis 48: 20–30. doi:10.1002/dvg.20578

McElyea SD, Starbuck JM, Tumbleson-Brink DM, Harrington E, Blazek JD,

Ghoneima A, Kula K, Roper RJ (2016) Influence of prenatal EGCG

treatment and Dyrk1a dosage reduction on craniofacial features

associated with Down syndrome. Hum Mol Genet 25: 4856–4869.

doi:10.1093/hmg/ddw309

Menon VR, Ananthapadmanabhan V, Swanson S, Saini S, Sesay F, Yakovlev V,

Florens L, DeCaprio JA, Washburn MP, Dozmorov M, et al (2019) DYRK1A

regulates the recruitment of 53BP1 to the sites of DNA damage in part

through interaction with RNF169. Cell Cycle 18: 531–551. doi:10.1080/

15384101.2019.1577525

Miyata Y, Nishida E (1999) Distantly related cousins of MAP kinase:

Biochemical properties and possible physiological functions.

Biochem Biophys Res Commun 266: 291–295. doi:10.1006/

bbrc.1999.1705

Miyata Y, Nishida E (2004) CK2 controls multiple protein kinases by

phosphorylating a kinase-targeting molecular chaperone Cdc37. Mol

Cell Biol 24: 4065–4074. doi:10.1128/MCB.24.9.4065-4074.2004

Miyata Y, Nishida E (2011) DYRK1A binds to an evolutionarily conserved WD40repeat protein WDR68 and induces its nuclear translocation. Biochim

Biophys Acta 1813: 1728–1739. doi:10.1016/j.bbamcr.2011.06.023

Miyata Y, Nishida E (2021) Protein quality control of DYRK family protein

kinases by the Hsp90-Cdc37 molecular chaperone. Biochim Biophys

Acta Mol Cell Res 1868: 119081. doi:10.1016/j.bbamcr.2021.119081

Miyata Y, Chambraud B, Radanyi C, Leclerc J, Lebeau M-C, Renoir J-M,

Shirai R, Catelli M-G, Yahara I, Baulieu E-E (1997) Phosphorylation

of the immunosuppressant FK506-binding protein FKBP52 by

casein kinase II: Regulation of HSP90-binding activity of FKBP52.

Proc Natl Acad Sci U S A 94: 14500–14505. doi:10.1073/

pnas.94.26.14500

Miyata Y, Akashi M, Nishida E (1999) Molecular cloning and characterization

of a novel member of the MAP kinase superfamily. Genes Cells 4:

299–309. doi:10.1046/j.1365-2443.1999.00261.x

Miyata Y, Ikawa Y, Shibuya M, Nishida E (2001) Specific association of a set of

molecular chaperones including HSP90 and Cdc37 with MOK, a

member of the mitogen-activated protein kinase superfamily. J Biol

Chem 276: 21841–21848. doi:10.1074/jbc.M010944200

Miyata Y, Shibata T, Aoshima M, Tsubata T, Nishida E (2014) The molecular

chaperone TRiC/CCT binds to the Trp-Asp 40 (WD40) repeat protein

WDR68 and promotes its folding, protein kinase DYRK1A binding, and

nuclear accumulation. J Biol Chem 289: 33320–33332. doi:10.1074/

jbc.M114.586115

Morita K, Lo Celso C, Spencer-Dene B, Zouboulis CC, Watt FM (2006) HAN11

binds mDia1 and controls GLI1 transcriptional activity. J Dermatol Sci

44: 11–20. doi:10.1016/j.jdermsci.2006.06.001

¨ N, Villiers B, Pani G, Karatas M,

Nguyen TL, Duchon A, Manousopoulou A, Loaec

Mechling AE, Harsan LA, Limanton E, et al (2018) Correction of

cognitive deficits in mouse models of Down syndrome by a

pharmacological inhibitor of DYRK1A. Dis Model Mech 11: dmm035634.

doi:10.1242/dmm.035634

Ori-McKenney KM, McKenney RJ, Huang HH, Li T, Meltzer S, Jan LY, Vale RD,

Wiita AP, Jan YN (2016) Phosphorylation of beta-tubulin by the Down

syndrome kinase, minibrain/DYRK1a, regulates microtubule

dynamics and dendrite morphogenesis. Neuron 90: 551–563.

doi:10.1016/j.neuron.2016.03.027

O’Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, Levy R, Ko A, Lee C,

Smith JD, et al (2012) Sporadic autism exomes reveal a highly

interconnected protein network of de novo mutations. Nature 485:

246–250. doi:10.1038/nature10989

FAM53C binds and inhibits DYRK1A in the cytoplasm

Miyata and Nishida

Papenfuss M, Lützow S, Wilms G, Babendreyer A, Flaßhoff M, Kunick C, Becker

W (2022) Differential maturation and chaperone dependence of the

paralogous protein kinases DYRK1A and DYRK1B. Sci Rep 12: 2393.

doi:10.1038/s41598-022-06423-0

Pennington KL, Chan TY, Torres MP, Andersen JL (2018) The dynamic and

stress-adaptive signaling hub of 14-3-3: Emerging mechanisms of

regulation and context-dependent protein-protein interactions.

Oncogene 37: 5587–5604. doi:10.1038/s41388-018-0348-3

Redhead Y, Gibbins D, Lana-Elola E, Watson-Scales S, Dobson L, Krause M, Liu

KJ, Fisher EMC, Green JBA, Tybulewicz VLJ (2023) Craniofacial

dysmorphology in Down syndrome is caused by increased dosage of

Dyrk1a and at least three other genes. Development 150: dev201077.

doi:10.1242/dev.201077

Ritterhoff S, Farah CM, Grabitzki J, Lochnit G, Skurat AV, Schmitz ML (2010) The

WD40-repeat protein Han11 functions as a scaffold protein to control

HIPK2 and MEKK1 kinase functions. EMBO J 29: 3750–3761. doi:10.1038/

emboj.2010.251

Roewenstrunk J, Di Vona C, Chen J, Borras E, Dong C, Arató K, Sabidó E, Huen

MSY, de la Luna S (2019) A comprehensive proteomics-based

interaction screen that links DYRK1A to RNF169 and to the DNA

damage response. Sci Rep 9: 6014. doi:10.1038/s41598-019-42445-x

Ryoo SR, Jeong HK, Radnaabazar C, Yoo JJ, Cho HJ, Lee HW, Kim IS, Cheon YH,

Ahn YS, Chung SH, et al (2007) DYRK1A-mediated

hyperphosphorylation of Tau. A functional link between Down

syndrome and Alzheimer disease. J Biol Chem 282: 34850–34857.

doi:10.1074/jbc.M707358200

Segal D, Maier S, Mastromarco GJ, Qian WW, Nabeel-Shah S, Lee H, Moore G,

Lacoste J, Larsen B, Lin ZY, et al (2023) A central chaperone-like role for

14-3-3 proteins in human cells. Mol Cell 83: 974–993.e15. doi:10.1016/

j.molcel.2023.02.018

Shen W, Taylor B, Jin Q, Nguyen-Tran V, Meeusen S, Zhang YQ, Kamireddy A,

Swafford A, Powers AF, Walker J, et al (2015) Inhibition of DYRK1A and

GSK3B induces human beta-cell proliferation. Nat Commun 6: 8372.

doi:10.1038/ncomms9372

Skurat AV, Dietrich AD (2004) Phosphorylation of Ser640 in muscle glycogen

synthase by DYRK family protein kinases. J Biol Chem 279: 2490–2498.

doi:10.1074/jbc.M301769200

Stirnimann CU, Petsalaki E, Russell RB, Müller CW (2010) WD40 proteins

propel cellular networks. Trends Biochem Sci 35: 565–574. doi:10.1016/

j.tibs.2010.04.003

Stotani S, Giordanetto F, Medda F (2016) DYRK1A inhibition as potential

treatment for Alzheimer’s disease. Future Med Chem 8: 681–696.

doi:10.4155/fmc-2016-0013

Tian T, Zhang Y, Wu T, Yang L, Chen C, Li N, Li Y, Xu S, Fu Z, Cui X, et al (2019)

miRNA profiling in the hippocampus of attention-deficit/

hyperactivity disorder rats. J Cell Biochem 120: 3621–3629. doi:10.1002/

jcb.27639

van Bon BW, Coe BP, Bernier R, Green C, Gerdts J, Witherspoon K, Kleefstra T,

Willemsen MH, Kumar R, Bosco P, et al (2016) Disruptive de novo

mutations of DYRK1A lead to a syndromic form of autism and ID. Mol

Psychiatry 21: 126–132. doi:10.1038/mp.2015.5

Varjosalo M, Keskitalo S, Van Drogen A, Nurkkala H, Vichalkovski A, Aebersold

R, Gstaiger M (2013) The protein interaction landscape of the human

CMGC kinase group. Cell Rep 3: 1306–1320. doi:10.1016/

j.celrep.2013.03.027

Viard J, Loe-Mie Y, Daudin R, Khelfaoui M, Plancon C, Boland A, Tejedor F,

Huganir RL, Kim E, Kinoshita M, et al (2022) Chr21 protein-protein

interactions: Enrichment in proteins involved in intellectual disability,

autism, and late-onset Alzheimer’s disease. Life Sci Alliance 5:

e202101205. doi:10.26508/lsa.202101205

¨ C, Sanchez´

Walter C, Marada A, Suhm T, Ernsberger R, Muders V, Kücükkose

Mart´ın P, Hu Z, Aich A, Loroch S, et al (2021) Global kinome profiling

reveals DYRK1A as critical activator of the human mitochondrial

https://doi.org/10.26508/lsa.202302129

vol 6 | no 12 | e202302129

16 of 17

import machinery. Nat Commun 12: 4284. doi:10.1038/s41467-02124426-9

Wang P, Alvarez-Perez JC, Felsenfeld DP, Liu H, Sivendran S, Bender A, Kumar

A, Sanchez R, Scott DK, Garcia-Ocaña A, et al (2015) A high-throughput

chemical screen reveals that harmine-mediated inhibition of DYRK1A

increases human pancreatic beta cell replication. Nat Med 21:

383–388. doi:10.1038/nm.3820

Wegiel J, Kuchna I, Nowicki K, Frackowiak J, Dowjat K, Silverman WP,

Reisberg B, DeLeon M, Wisniewski T, Adayev T, et al (2004) Cell typeand brain structure-specific patterns of distribution of minibrain

kinase in human brain. Brain Res 1010: 69–80. doi:10.1016/

j.brainres.2004.03.008

Woods YL, Cohen P, Becker W, Jakes R, Goedert M, Wang X, Proud CG (2001)

The kinase DYRK phosphorylates protein-synthesis initiation

factor eIF2Bepsilon at Ser539 and the microtubule-associated

protein tau at Thr212: Potential role for DYRK as a glycogen

FAM53C binds and inhibits DYRK1A in the cytoplasm

Miyata and Nishida

synthase kinase 3-priming kinase. Biochem J 355: 609–615.

doi:10.1042/bj3550609

Yu D, Cattoglio C, Xue Y, Zhou Q (2019) A complex between DYRK1A and DCAF7

phosphorylates the C-terminal domain of RNA polymerase II to

promote myogenesis. Nucleic Acids Res 47: 4462–4475. doi:10.1093/

nar/gkz162

Zou Y, Lim S, Lee K, Deng X, Friedman E (2003) Serine/threonine kinase Mirk/

Dyrk1B is an inhibitor of epithelial cell migration and is negatively

regulated by the Met adaptor Ran-binding protein M. J Biol Chem 278:

49573–49581. doi:10.1074/jbc.M307556200

License: This article is available under a Creative

Commons License (Attribution 4.0 International, as

described at https://creativecommons.org/

licenses/by/4.0/).

https://doi.org/10.26508/lsa.202302129

vol 6 | no 12 | e202302129

17 of 17

...