Reviewed, UniProtKB/Swiss-Prot Q9ESL4 (MLTK_MOUSE)

Names and origin

Protein names

Recommended name:
    Mitogen-activated protein kinase kinase kinase MLT
    EC=2.7.11.25
Alternative name(s):
    MLK-like mitogen-activated protein triple kinase
    Leucine zipper- and sterile alpha motif kinase ZAK
    Sterile alpha motif- and leucine zipper-containing kinase AZK
    Mixed lineage kinase-related kinase
      Short name=MLK-related kinase
      Short name=MRK

Gene names

Name:

Mltk

Organism

Mus musculus (Mouse)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus

Protein attributes

Sequence length	802 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Stress-activated component of a protein kinase signal transduction cascade. Regulates the JNK and p38 pathways. Pro-apoptotic. Role in regulation of S and G2 cell cycle checkpoint by direct phosphorylation of CHEK2. Isoform 1, but not isoform 2, phosphorylates histone H3 at 'Ser-28'. Ref.1 UniProtKB Q9NYL2
Catalytic activity	ATP + a protein = ADP + a phosphoprotein. Ref.1
Cofactor	Magnesium. Ref.1
Enzyme regulation	Activated by phosphorylation by PKN1 and autophosphorylation on Thr-161 and Ser-165 By similarity. UniProtKB Q9NYL2
Subunit structure	Homodimer. Interacts with PKN1 and ZNF33A By similarity. Ref.1
Subcellular location	Cytoplasm. Nucleus. Note: Appears to shuttle between nucleus and cytoplasm. Ref.1
Sequence similarities	Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily. Contains 1 protein kinase domain. Contains 1 SAM (sterile alpha motif) domain.

Ontologies

Keywords
Biological process	Cell cycle
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Alternative splicing
Ligand	ATP-binding Magnesium Metal-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Technical term	Direct protein sequencing
Gene Ontology (GO)
Biological process	cell cycle Inferred from electronic annotation. Source: UniProtKB-KW cell cycle checkpoint Inferred from sequence or structural similarity. Source: UniProtKB cytoskeleton organization Ref.1 Inferred from direct assay. Source: MGI positive regulation of apoptosis Inferred from sequence or structural similarity. Source: UniProtKB protein amino acid phosphorylation Ref.1 Inferred from direct assay. Source: UniProtKB protein kinase cascade Ref.1 Inferred from direct assay. Source: UniProtKB
Cellular component	cytoplasm Ref.1 Inferred from direct assay. Source: UniProtKB nucleus Ref.1 Inferred from direct assay. Source: MGI
Molecular function	ATP binding Ref.1 Inferred from direct assay. Source: UniProtKB MAP kinase kinase kinase activity Ref.1 Inferred from direct assay. Source: MGI magnesium ion binding Ref.1 Inferred from direct assay. Source: UniProtKB protein tyrosine kinase activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 Ref.1 (identifier: Q9ESL4-1)

Also known as: Alpha;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 Ref.1 (identifier: Q9ESL4-2)

Also known as: Beta;

The sequence of this isoform differs from the canonical sequence as follows:
     332-454: PSFEIGAWTE...HLKPGTGPQD → LPLSARMSEE...DAENDVDNSE
     455-802: Missing.

Note: Phosphorylated at Ser-434 and Ser-453 (By similarity).

Isoform 3 (identifier: Q9ESL4-3)

The sequence of this isoform differs from the canonical sequence as follows:
     285-289: CEIEA → WVAPA
     290-802: Missing.

Note: No experimental confirmation available.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 802	802	Mitogen-activated protein kinase kinase kinase MLT		PRO_0000086339
Regions
	Domain	16 – 277	262	Protein kinase
	Domain	287 – 308	22	Leucine-zipper UniProtKB P80192
	Domain	339 – 410	72	SAM
	Nucleotide binding	22 – 30	9	ATP By similarity UniProtKB P80192
Sites
	Active site	133	1	Proton acceptor By similarity UniProtKB P80192
	Binding site	45	1	ATP By similarity UniProtKB Q9NYL2
Amino acid modifications
	Modified residue	3	1	Phosphoserine By similarity
	Modified residue	161	1	Phosphothreonine; by autocatalysis By similarity UniProtKB Q9NYL2
	Modified residue	165	1	Phosphoserine; by autocatalysis By similarity UniProtKB Q9NYL2
	Modified residue	275	1	Phosphoserine By similarity
	Modified residue	302	1	Phosphoserine By similarity
	Modified residue	328	1	Phosphothreonine By similarity
	Modified residue	591	1	Phosphoserine By similarity
	Modified residue	593	1	Phosphoserine By similarity
	Modified residue	599	1	Phosphoserine By similarity
	Modified residue	628	1	Phosphothreonine By similarity
	Modified residue	634	1	Phosphoserine By similarity
	Modified residue	636	1	Phosphoserine Ref.5
	Modified residue	638	1	Phosphoserine By similarity
	Modified residue	640	1	Phosphothreonine Ref.5
	Modified residue	687	1	Phosphoserine Ref.6
	Modified residue	691	1	Phosphoserine By similarity
	Modified residue	727	1	Phosphoserine By similarity
	Modified residue	733	1	Phosphoserine By similarity
Natural variations
	Alternative sequence	285 – 289	5	CEIEA → WVAPA in isoform 3.		VSP_051747
	Alternative sequence	290 – 802	513	Missing in isoform 3.		VSP_051748
	Alternative sequence	332 – 454	123	PSFEI…TGPQD → LPLSARMSEESYFESKTEES NSAEMSCQITAASNGEGHGM NPGLQAMMLMGFGDVFSMNK AGAVLHSGMQINMQAKQNSS KTTCKRRGKKVNMALGFSDF DLSEGDDDDHDGDDAENDVD NSE in isoform 2. Ref.1		VSP_051745
	Alternative sequence	455 – 802	348	Missing in isoform 2. Ref.1		VSP_051746
Experimental info
	Mutagenesis	45	1	K → M: Loss of kinase activity. Ref.1
	Sequence conflict	171	1	P → Q in BAC32371. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (Alpha) [UniParc]. Last modified March 1, 2001. Version 1. Checksum: D431DF8F312A43CC	FASTA	802	91,720
	10 20 30 40 50 60 MSSLGASFVQ IKFDDLQFFE NCGGGSFGSV YRAKWISQDK EVAVKKLLKI EKEAEILSVL 70 80 90 100 110 120 SHRNIIQFYG VILEPPNYGI VTEYASLGSL YDYINSNRSE EMDMEHIMTW ATDVAKGMHY 130 140 150 160 170 180 LHMEAPVKVI HRDLKSRNVV IAADGVLKIC DFGASRFHNH TTHMSLVGTF PWMAPEVIQS 190 200 210 220 230 240 LPVSETCDTY SYGVVLWEML TREVPFKGLE GLQVAWLVVE KNERLTIPSS CPRSFAELLH 250 260 270 280 290 300 QCWEADAKKR PSFKQIISIL ESMSNDTNLP DQCNSFLHNK AEWRCEIEAT LERLKKLERD 310 320 330 340 350 360 LSFKEQELKE RERRLKMWEQ KLTEQSNTPL LPSFEIGAWT EDDVYFWVQQ LVRKGESSVE 370 380 390 400 410 420 MSGYASLFKE NNITGKRLLL LEEEDLKDMG IVSKGHIIHF KSAIEKLTHD YLNLFHFPPL 430 440 450 460 470 480 IKDSGGEPEE NEEKIVNLEL VFGFHLKPGT GPQDCKWKMY MEMDGDEVAI TYIKDVTFNT 490 500 510 520 530 540 SLPDAEILKM TKPPFVMEKW IVGIAEDQTV ECTVTYENDV RTPKLTKHVH SIQWDRTKPQ 550 560 570 580 590 600 DEVKAVQLAI QTLFSSSEGN PGSRSDSSAD CQWLDTLRMR QIASHTSLQR SQSNPILGSP 610 620 630 640 650 660 FFPYFANQDS YAAAVRRTQT PVKYQQITPS INPSRSSSPT QYGLSRNFSS LNLSSRDSGF 670 680 690 700 710 720 SSLNDSSSER GRYSDRSRNK YYRGSVSLNS SPKGRYGGKS QHSTPSRERY SGKFYRLPQS 730 740 750 760 770 780 ALNTHQSPDF KRSPNDHDRR VPRTIPGMPL HPETASKAGE EESRVSEGGW TKVEYRKKTH 790 800 RQLSAKTSKE RTRGNYRGRR NF
	Isoform 2 (Beta). Checksum: 35C2FC0D729D9395	FASTA	454	51,366
	10 20 30 40 50 60 MSSLGASFVQ IKFDDLQFFE NCGGGSFGSV YRAKWISQDK EVAVKKLLKI EKEAEILSVL 70 80 90 100 110 120 SHRNIIQFYG VILEPPNYGI VTEYASLGSL YDYINSNRSE EMDMEHIMTW ATDVAKGMHY 130 140 150 160 170 180 LHMEAPVKVI HRDLKSRNVV IAADGVLKIC DFGASRFHNH TTHMSLVGTF PWMAPEVIQS 190 200 210 220 230 240 LPVSETCDTY SYGVVLWEML TREVPFKGLE GLQVAWLVVE KNERLTIPSS CPRSFAELLH 250 260 270 280 290 300 QCWEADAKKR PSFKQIISIL ESMSNDTNLP DQCNSFLHNK AEWRCEIEAT LERLKKLERD 310 320 330 340 350 360 LSFKEQELKE RERRLKMWEQ KLTEQSNTPL LLPLSARMSE ESYFESKTEE SNSAEMSCQI 370 380 390 400 410 420 TAASNGEGHG MNPGLQAMML MGFGDVFSMN KAGAVLHSGM QINMQAKQNS SKTTCKRRGK 430 440 450 KVNMALGFSD FDLSEGDDDD HDGDDAENDV DNSE
	Isoform 3. Checksum: 440E5651076A04A4	FASTA	289	32,842
	10 20 30 40 50 60 MSSLGASFVQ IKFDDLQFFE NCGGGSFGSV YRAKWISQDK EVAVKKLLKI EKEAEILSVL 70 80 90 100 110 120 SHRNIIQFYG VILEPPNYGI VTEYASLGSL YDYINSNRSE EMDMEHIMTW ATDVAKGMHY 130 140 150 160 170 180 LHMEAPVKVI HRDLKSRNVV IAADGVLKIC DFGASRFHNH TTHMSLVGTF PWMAPEVIQS 190 200 210 220 230 240 LPVSETCDTY SYGVVLWEML TREVPFKGLE GLQVAWLVVE KNERLTIPSS CPRSFAELLH 250 260 270 280 QCWEADAKKR PSFKQIISIL ESMSNDTNLP DQCNSFLHNK AEWRWVAPA

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Identification and characterization of a novel MAP kinase kinase kinase, MLTK." Gotoh I., Adachi M., Nishida E. J. Biol. Chem. 276:4276-4286(2001) [PubMed: 11042189] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), FUNCTION, SUBCELLULAR LOCATION, AUTOPHOSPHORYLATION, HOMODIMERIZATION, MUTAGENESIS OF LYS-45. Tissue: Heart.
[2]	"The transcriptional landscape of the mammalian genome." Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y. Science 309:1559-1563(2005) [PubMed: 16141072] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3). Strain: C57BL/6J. Tissue: Head.
[3]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Strain: FVB/N. Tissue: Mammary gland.
[4]	Lubec G., Kang S.U. Submitted (APR-2007) to UniProtKB Cited for: PROTEIN SEQUENCE OF 225-233, MASS SPECTROMETRY. Strain: C57BL/6. Tissue: Brain.
[5]	"Large-scale phosphorylation analysis of mouse liver." Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007) [PubMed: 17242355] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-636 AND THR-640, MASS SPECTROMETRY. Tissue: Liver.
[6]	"Solid tumor proteome and phosphoproteome analysis by high resolution mass spectrometry." Zanivan S., Gnad F., Wickstroem S.A., Geiger T., Macek B., Cox J., Faessler R., Mann M. J. Proteome Res. 7:5314-5326(2008) [PubMed: 18973353] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-687, MASS SPECTROMETRY.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBLGenBankDDBJ	AB049731 mRNA. Translation: BAB16442.1. AB049732 mRNA. Translation: BAB16443.1. AK045444 mRNA. Translation: BAC32371.1. AK132186 mRNA. Translation: BAE21021.1. BC023718 mRNA. Translation: AAH23718.1.
IPI	IPI00265705. IPI00274639. IPI00607999.
RefSeq	NP_001158263.1. NP_075544.1. NP_835185.2.
UniGene	Mm.314618 Mm.389773
3D structure databases
HSSP	HSSP built from PDB template 1VR2 based on UniProtKB P35968.
ModBase	Search...
Protein-protein interaction databases
STRING	Q9ESL4.
PTM databases
PhosphoSite	Q9ESL4.
Proteomic databases
PRIDE	Q9ESL4.
Genome annotation databases
Ensembl	ENSMUST00000090824; ENSMUSP00000088334; ENSMUSG00000004085; Mus musculus. [Genome view] ENSMUST00000112073; ENSMUSP00000107704; ENSMUSG00000004085; Mus musculus. [Genome view]
GeneID	65964.
KEGG	mmu:65964.
UCSC	uc008kbs.1. mouse. uc008kbu.1. mouse. uc008kbv.1. mouse.
Organism-specific databases
MGI	MGI:2443258. B230120H23Rik.
Phylogenomic databases
HOGENOM	Q9ESL4.
HOVERGEN	Q9ESL4.
OMA	CTVTYES.
Enzyme and pathway databases
BRENDA	2.7.11.25. 244.
Gene expression databases
ArrayExpress	Q9ESL4.
Bgee	Q9ESL4.
CleanEx	MM_B230120H23RIK.
Genevestigator	Q9ESL4.
GermOnline	ENSMUSG00000004085. Mus musculus.
Family and domain databases
InterPro	IPR000719. Prot_kinase_core. IPR017441. Protein_kinase_ATP_BS. IPR001660. SAM. IPR013761. SAM_type. IPR008271. Ser_thr_pkin_AS. IPR001245. Tyr_pkinase. [Graphical view]
Gene3D	G3DSA:1.10.150.50. SAM_type. 1 hit.
Pfam	PF07714. Pkinase_Tyr. 1 hit. PF00536. SAM_1. 1 hit. [Graphical view]
PRINTS	PR00109. TYRKINASE.
ProDom	PD000001. Prot_kinase. 1 hit. [Graphical view] [Entries sharing at least one domain]
SMART	SM00454. SAM. 1 hit. [Graphical view]
PROSITE	PS00107. PROTEIN_KINASE_ATP. False negative. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. PS50105. SAM_DOMAIN. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	320398.
SOURCE	Search...

Entry information

Entry name

MLTK_MOUSE

Accession

Primary (citable) accession number: Q9ESL4
Secondary accession number(s): Q3V1X8, Q8BR73, Q9ESL3

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 5, 2005
Last sequence update:	March 1, 2001
Last modified:	November 3, 2009
This is version 75 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)