Q9Y4R8 (TELO2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Telomere length regulation protein TEL2 homolog

Alternative name(s):
Protein clk-2 homolog
Short name=hCLK2

Gene names

Name:	TELO2
Synonyms:	KIAA0683

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	837 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Regulator of the DNA damage response (DDR). Part of the TTT complex that is required to stabilize protein levels of the phosphatidylinositol 3-kinase-related protein kinase (PIKK) family proteins. The TTT complex is involved in the cellular resistance to DNA damage stresses, like ionizing radiation (IR), ultraviolet (UV) and mitomycin C (MMC). Together with the TTT complex and HSP90 may participate in the proper folding of newly synthesized PIKKs. Promotes assembly, stabilizes and maintains the activity of mTORC1 and mTORC2 complexes, which regulate cell growth and survival in response to nutrient and hormonal signals. May be involved in telomere length regulation. Ref.8 Ref.10
Subunit structure	Component of the TTT complex composed of TELO2, TTI1 and TTI2. Interacts with ATM, ATR, MTOR, PRKDC, RUVBL2, TTI1, TTI2, SMG1 and TRRAP. Component of the mTORC1 and mTORC2 complexes. Ref.10 Ref.11 Ref.12 Ref.17
Subcellular location	Cytoplasm. Membrane. Nucleus. Chromosome › telomere Probable Ref.8 Ref.17.
Post-translational modification	Hydroxylation by PHD3 is required for a proper interaction with ATR, and activation of the ATR/CHK1/p53 pathway following DNA damage. Phosphorylated at Ser-485 by CK2 following growth factor deprivation, leading to its subsequent ubiquitination by the SCF(FBXO9) complex. Phosphorylation by CK2 only takes place when TELO2 is bound to mTORC1, not mTORC2; leading to selective ubiquitination of mTORC1-associated protein. Ref.17 Ubiquitinated by the SCF(FBXO9) complex following phosphorylation by CK2 in response to growth factor deprivation, leading to its degradation by the proteasome. Only mTORC1-associated protein is ubiquitinated and degraded, leading to selective inactivation of mTORC1 to restrain cell growth and protein translation, while mTORC2 is activated due to the relief of feedback inhibition by mTORC1. Ref.17
Miscellaneous	Cells overexpressing TELO2 are hypersensitive to hydroxyurea (HU) and undergo apoptotic death in response to treatment with HU.
Sequence similarities	Belongs to the TEL2 family.
Sequence caution	The sequence BAA31658.3 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.

Ontologies

Keywords
Cellular component	Chromosome Cytoplasm Membrane Nucleus Telomere
Coding sequence diversity	Polymorphism
PTM	Hydroxylation Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	regulation of TOR signaling cascade Inferred from mutant phenotype Ref.17. Source: UniProtKB
Cellular_component	TORC1 complex Inferred from direct assay Ref.17. Source: UniProtKB TORC2 complex Inferred from direct assay Ref.17. Source: UniProtKB chromosome, telomeric region Inferred from electronic annotation. Source: UniProtKB-SubCell cytoplasm Inferred from direct assay Ref.17. Source: UniProtKB membrane Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Inferred from direct assay. Source: HPA
Molecular_function	protein complex binding Inferred from direct assay PubMed 20864032. Source: MGI
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
ATM	Q13315	4	EBI-1043674,EBI-495465
TTI1	O43156	7	EBI-1043674,EBI-1055680

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 837	837	Telomere length regulation protein TEL2 homolog		PRO_0000318515
Amino acid modifications
	Modified residue	374	1	Hydroxyproline
	Modified residue	419	1	Hydroxyproline
	Modified residue	422	1	Hydroxyproline
	Modified residue	456	1	Phosphoserine By similarity
	Modified residue	485	1	Phosphoserine; by CK2 Ref.17
	Modified residue	487	1	Phosphoserine Ref.17
	Modified residue	491	1	Phosphoserine Ref.17
	Modified residue	688	1	Phosphoserine Ref.13
	Modified residue	836	1	Phosphoserine Ref.15
Natural variations
	Natural variant	7	1	E → G. Corresponds to variant rs2667661 [ dbSNP | Ensembl ].		VAR_038752
	Natural variant	7	1	E → Q. Corresponds to variant rs2667660 [ dbSNP | Ensembl ].		VAR_061839
	Natural variant	146	1	Q → R. Ref.2 Ref.3 Ref.6 Ref.7 Corresponds to variant rs2235624 [ dbSNP | Ensembl ].		VAR_038753
	Natural variant	511	1	A → V. Corresponds to variant rs58099766 [ dbSNP | Ensembl ].		VAR_061840
	Natural variant	674	1	Q → R. Corresponds to variant rs2248128 [ dbSNP | Ensembl ].		VAR_038754
Experimental info
	Mutagenesis	485	1	S → A: Abolishes phosphorylation by CK2 in response to growth factor deprivation and subsequent ubiquitination and degradation. Ref.17
	Sequence conflict	7	1	E → R in BAA31658. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Q9Y4R8 [UniParc]. Last modified February 5, 2008. Version 2. Checksum: 76CB619C73C1F1A7	FASTA	837	91,747
	10 20 30 40 50 60 MEPAPSEVRL AVREAIHALS SSEDGGHIFC TLESLKRYLG EMEPPALPRE KEEFASAHFS 70 80 90 100 110 120 PVLRCLASRL SPAWLELLPH GRLEELWASF FLEGPADQAF LVLMETIEGA AGPSFRLMKM 130 140 150 160 170 180 ARLLARFLRE GRLAVLMEAQ CRQQTQPGFI LLRETLLGKV VALPDHLGNR LQQENLAEFF 190 200 210 220 230 240 PQNYFRLLGE EVVRVLQAVV DSLQGGLDSS VSFVSQVLGK ACVHGRQQEI LGVLVPRLAA 250 260 270 280 290 300 LTQGSYLHQR VCWRLVEQVP DRAMEAVLTG LVEAALGPEV LSRLLGNLVV KNKKAQFVMT 310 320 330 340 350 360 QKLLFLQSRL TTPMLQSLLG HLAMDSQRRP LLLQVLKELL ETWGSSSAIR HTPLPQQRHV 370 380 390 400 410 420 SKAVLICLAQ LGEPELRDSR DELLASMMAG VKCRLDSSLP PVRRLGMIVA EVVSARIHPE 430 440 450 460 470 480 GPPLKFQYEE DELSLELLAL ASPQPAGDGA SEAGTSLVPA TAEPPAETPA EIVDGGVPQA 490 500 510 520 530 540 QLAGSDSDLD SDDEFVPYDM SGDRELKSSK APAYVRDCVE ALTTSEDIER WEAALRALEG 550 560 570 580 590 600 LVYRSPTATR EVSVELAKVL LHLEEKTCVV GFAGLRQRAL VAVTVTDPAP VADYLTSQFY 610 620 630 640 650 660 ALNYSLRQRM DILDVLTLAA QELSRPGCLG RTPQPGSPSP NTPCLPEAAV SQPGSAVASD 670 680 690 700 710 720 WRVVVEERIR SKTQRLSKGG PRQGPAGSPS RFNSVAGHFF FPLLQRFDRP LVTFDLLGED 730 740 750 760 770 780 QLVLGRLAHT LGALMCLAVN TTVAVAMGKA LLEFVWALRF HIDAYVRQGL LSAVSSVLLS 790 800 810 820 830 LPAARLLEDL MDELLEARSW LADVAEKDPD EDCRTLALRA LLLLQRLKNR LLPPASP

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Prediction of the coding sequences of unidentified human genes. X. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro." Ishikawa K., Nagase T., Suyama M., Miyajima N., Tanaka A., Kotani H., Nomura N., Ohara O. DNA Res. 5:169-176(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Brain.
[2]	"Towards a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs." Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S., Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H., Lauber J., Duesterhoeft A., Beyer A., Koehrer K., Strack N., Mewes H.-W., Ottenwaelder B., Obermaier B. , Tampe J., Heubner D., Wambutt R., Korn B., Klein M., Poustka A. Genome Res. 11:422-435(2001) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT ARG-146. Tissue: Testis.
[3]	"The full-ORF clone resource of the German cDNA consortium." Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., Wiemann S., Schupp I. BMC Genomics 8:399-399(2007) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT ARG-146. Tissue: Testis.
[4]	"Sequence, structure and pathology of the fully annotated terminal 2 Mb of the short arm of human chromosome 16." Daniels R.J., Peden J.F., Lloyd C., Horsley S.W., Clark K., Tufarelli C., Kearney L., Buckle V.J., Doggett N.A., Flint J., Higgs D.R. Hum. Mol. Genet. 10:339-352(2001) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"The sequence and analysis of duplication-rich human chromosome 16." Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J. , Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J., Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D., Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M., Rubin E.M., Pennacchio L.A. Nature 432:988-994(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], VARIANT ARG-146.
[7]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT ARG-146. Tissue: Placenta.
[8]	"Human CLK2 links cell cycle progression, apoptosis, and telomere length regulation." Jiang N., Benard C.Y., Kebir H., Shoubridge E.A., Hekimi S. J. Biol. Chem. 278:21678-21684(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION.
[9]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Cervix carcinoma.
[10]	"A genetic screen identifies the Triple T complex required for DNA damage signaling and ATM and ATR stability." Hurov K.E., Cotta-Ramusino C., Elledge S.J. Genes Dev. 24:1939-1950(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH TTI1 AND TTI2.
[11]	"Tel2 structure and function in the Hsp90-dependent maturation of mTOR and ATR complexes." Takai H., Xie Y., de Lange T., Pavletich N.P. Genes Dev. 24:2019-2030(2010) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH ATM; ATR; MTOR; PRKDC; RUVBL2; TTI1 AND TTI2.
[12]	"Tti1 and Tel2 are critical factors in mammalian target of rapamycin complex assembly." Kaizuka T., Hara T., Oshiro N., Kikkawa U., Yonezawa K., Takehana K., Iemura S., Natsume T., Mizushima N. J. Biol. Chem. 285:20109-20116(2010) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH TTI1; MTOR; ATM; ATR; PRKDC; SMG1 AND TRRAP.
[13]	"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis." Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M. Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-688, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[14]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[15]	"System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation." Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B. Sci. Signal. 4:RS3-RS3(2011) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-836, MASS SPECTROMETRY.
[16]	"PHD3-dependent hydroxylation of HCLK2 promotes the DNA damage response." Xie L., Pi X., Mishra A., Fong G., Peng J., Patterson C. J. Clin. Invest. 122:2827-2836(2012) [PubMed] [Europe PMC] [Abstract] Cited for: HYDROXYLATION AT PRO-374; PRO-419 AND PRO-422 BY PHD3.
[17]	"SCF(Fbxo9) and CK2 direct the cellular response to growth factor withdrawal via Tel2/Tti1 degradation and promote survival in multiple myeloma." Fernandez-Saiz V., Targosz B.S., Lemeer S., Eichner R., Langer C., Bullinger L., Reiter C., Slotta-Huspenina J., Schroeder S., Knorn A.M., Kurutz J., Peschel C., Pagano M., Kuster B., Bassermann F. Nat. Cell Biol. 15:72-81(2013) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION IN THE MTORC1 COMPLEX, IDENTIFICATION IN THE MTORC2 COMPLEX, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-485; SER-487 AND SER-491, UBIQUITINATION, MUTAGENESIS OF SER-485.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AB014583 mRNA. Translation: BAA31658.3. Different initiation. AL080126 mRNA. Translation: CAB45724.1. AL137394 mRNA. Translation: CAB70722.1. AE006467 Genomic DNA. Translation: AAK61284.1. AL031705 Genomic DNA. Translation: CAC37283.1. CH471112 Genomic DNA. Translation: EAW85647.1. CH471112 Genomic DNA. Translation: EAW85649.1. CH471112 Genomic DNA. Translation: EAW85650.1. BC017188 mRNA. Translation: AAH17188.1.
IPI	IPI00016868.
PIR	T12514.
RefSeq	NP_057195.2. NM_016111.3.
UniGene	Hs.271044.
3D structure databases
ProteinModelPortal	Q9Y4R8.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q9Y4R8. 17 interactions.
STRING	9606.ENSP00000262319.
PTM databases
PhosphoSite	Q9Y4R8.
Polymorphism databases
DMDM	166987394.
Proteomic databases
PaxDb	Q9Y4R8.
PRIDE	Q9Y4R8.
Protocols and materials databases
DNASU	9894.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000262319; ENSP00000262319; ENSG00000100726.
GeneID	9894.
KEGG	hsa:9894.
UCSC	uc002cly.3. human.
Organism-specific databases
CTD	9894.
GeneCards	GC16P001543.
H-InvDB	HIX0012685.
HGNC	HGNC:29099. TELO2.
HPA	HPA041348. HPA041473.
MIM	611140. gene.
neXtProt	NX_Q9Y4R8.
PharmGKB	PA162405604.
HUGE	Search...
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG327559.
HOGENOM	HOG000154542.
HOVERGEN	HBG108557.
InParanoid	Q9Y4R8.
KO	K11137.
OMA	HGRQKEI.
OrthoDB	EOG42JNQW.
Gene expression databases
ArrayExpress	Q9Y4R8.
Bgee	Q9Y4R8.
CleanEx	HS_TELO2.
Genevestigator	Q9Y4R8.
Family and domain databases
InterPro	IPR019337. Telomere_length_regulation_dom. [Graphical view]
Pfam	PF10193. Telomere_reg-2. 1 hit. [Graphical view]
ProtoNet	Search...
Other
ChiTaRS	TELO2. human.
GenomeRNAi	9894.
NextBio	37303.
SOURCE	Search...

Entry information

Entry name

TELO2_HUMAN

Accession

Primary (citable) accession number: Q9Y4R8
Secondary accession number(s): D3DU73 , O75168, Q7LDV4, Q9BR21

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 5, 2008
Last sequence update:	February 5, 2008
Last modified:	May 1, 2013
This is version 99 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.