Q95UN8 (M3KSL_DROME) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Mitogen-activated protein kinase kinase kinase
EC=2.7.11.25

Alternative name(s):
Mixed lineage kinase
Protein slipper
dMLK

Gene names

Name:	slpr
Synonyms:	Mlk2
ORF Names:	CG2272

Organism

Drosophila melanogaster (Fruit fly) [Reference proteome]

Taxonomic identifier

7227 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Protostomia › Ecdysozoa › Panarthropoda › Arthropoda › Mandibulata › Pancrustacea › Hexapoda › Insecta › Dicondylia › Pterygota › Neoptera › Endopterygota › Diptera › Brachycera › Muscomorpha › Eremoneura › Cyclorrhapha › Schizophora › Acalyptratae › Ephydroidea › Drosophilidae › Drosophilinae › Drosophilini › Drosophilina › Drosophiliti › Drosophila › Sophophora › melanogaster group › melanogaster subgroup

Protein attributes

Sequence length	1161 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Activates the JUN N-terminal pathway during dorsal closure. Ref.1 Ref.5 Ref.6
Catalytic activity	ATP + a protein = ADP + a phosphoprotein. Ref.5
Cofactor	Magnesium By similarity. UniProtKB P80192
Enzyme regulation	Homodimerization via the leucine zipper domains is required for autophosphorylation and subsequent activation By similarity. Activated by C6-ceramide. Ref.6 UniProtKB Q16584
Subunit structure	Homodimer By similarity. UniProtKB Q16584
Tissue specificity	Expressed both maternally and zygotically. Expressed uniformly in large quantities in the early embryo (stages 1-4). In the late embryo, expression is ubiquitous, but expression levels are dramatically reduced. Expressed in the adult head and thorax, and in S2 cells. Ref.5
Post-translational modification	Autophosphorylation on serine and threonine residues within the activation loop plays a role in enzyme activation By similarity. UniProtKB Q16584
Disruption phenotype	Mutants display defects in dorsal closure, resulting in a cuticle that resembles an open shoe. Therefore the protein was given the name Slipper. 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 SH3 domain.
Sequence caution	The sequence AAF46344.3 differs from that shown. Reason: Erroneous gene model prediction.

Ontologies

Keywords
Domain	Repeat SH3 domain
Ligand	ATP-binding Nucleotide-binding
Molecular function	Developmental protein Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	activation of JUN kinase activity Inferred from mutant phenotype Ref.6. Source: UniProtKB cellular response to ethanol Inferred from mutant phenotype PubMed 16451733. Source: FlyBase dorsal appendage formation Inferred from mutant phenotype PubMed 16888342. Source: FlyBase dorsal closure, elongation of leading edge cells Inferred from mutant phenotype Ref.1. Source: FlyBase imaginal disc fusion, thorax closure Inferred from mutant phenotype PubMed 16888342. Source: FlyBase imaginal disc-derived female genitalia morphogenesis Inferred from mutant phenotype PubMed 16888342. Source: FlyBase imaginal disc-derived male genitalia morphogenesis Inferred from mutant phenotype PubMed 16888342. Source: FlyBase positive regulation of JNK cascade Inferred from mutant phenotype PubMed 16451733PubMed 16888342. Source: FlyBase protein autophosphorylation Inferred from sequence or structural similarity Ref.1. Source: UniProtKB response to heat Inferred from mutant phenotype PubMed 22848763. Source: FlyBase
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW JUN kinase kinase kinase activity Inferred from direct assay Ref.5. Source: UniProtKB protein homodimerization activity Inferred from sequence or structural similarity Ref.1. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 1161	1161	Mitogen-activated protein kinase kinase kinase		PRO_0000086269
Regions
	Domain	56 – 120	65	SH3
	Domain	142 – 402	261	Protein kinase
	Nucleotide binding	148 – 156	9	ATP By similarity UniProtKB Q02779
	Region	426 – 447	22	Leucine-zipper 1
	Region	461 – 482	22	Leucine-zipper 2
	Compositional bias	21 – 39	19	Gln-rich
	Compositional bias	637 – 712	76	Asn-rich
	Compositional bias	978 – 1009	32	Ser-rich
Sites
	Active site	264	1	Proton acceptor By similarity UniProtKB Q02779
	Binding site	169	1	ATP Ref.6
Amino acid modifications
	Modified residue	300	1	Phosphothreonine; by autocatalysis By similarity UniProtKB Q16584
	Modified residue	304	1	Phosphoserine; by autocatalysis By similarity UniProtKB Q16584
	Modified residue	525	1	Phosphoserine Ref.7 UniProtKB Q16584
	Modified residue	560	1	Phosphoserine By similarity UniProtKB Q16584
	Modified residue	685	1	Phosphoserine By similarity UniProtKB Q16584
	Modified residue	773	1	Phosphoserine By similarity UniProtKB Q16584
	Modified residue	792	1	Phosphoserine By similarity UniProtKB Q16584
	Modified residue	862	1	Phosphothreonine Ref.7
	Modified residue	993	1	Phosphoserine By similarity UniProtKB Q16584
Experimental info
	Mutagenesis	169	1	K → A: Loss of kinase activity. Attenuates bsk activation. Ref.6
	Sequence conflict	327	1	D → Y in AAM50203. Ref.4
	Sequence conflict	670	1	S → P in AAL08011. Ref.5
	Sequence conflict	908	1	E → G in AAL08011. Ref.5

Sequences

	Sequence		Length	Mass (Da)
	Q95UN8 [UniParc]. Last modified December 1, 2001. Version 1. Checksum: DD6C7ABAC08EDA24	FASTA	1,161	128,961
	10 20 30 40 50 60 MPSQVSRGLD TTNMLPISEE QQLQQQQQQQ QLEQLHHPQI PEIPIPDLEQ VETQVGDGSL 70 80 90 100 110 120 WTALYDYDAQ GEDELTLRRG EIVVVLSTDS EVSGDVGWWT GKIGDKVGVF PKDFVTDEDP 130 140 150 160 170 180 LQLNVSSAIG DIQPHEIEYN ELDIKEVIGS GGFCKVHRGY YDGEEVAIKI AHQTGEDDMQ 190 200 210 220 230 240 RMRDNVLQEA KLFWALKHEN IAALRGVCLN TKLCLVMEYA RGGSLNRILA GKIPPDVLVN 250 260 270 280 290 300 WAIQIARGMN YLHNEAPMSI IHRDLKSSNV LIYEAIEGNH LQQKTLKITD FGLAREMYNT 310 320 330 340 350 360 QRMSAAGTYA WMPPEVISVS TYSKFSDVWS YGVLLWELIT GETPYKGFDP LSVAYGVAVN 370 380 390 400 410 420 TLTLPIPKTC PETWGALMKS CWQTDPHKRP GFKEILKQLE SIACSKFTLT PQESFHYMQE 430 440 450 460 470 480 CWRKEIAGVL HDLREKEKEL RNKEEQLLRV QNEQREKANL LKIREQNLRE RERVLIEREL 490 500 510 520 530 540 VMLQPVPSKR KHKKGKKNKP LQISLPTGFR HTITAVRDKA EQPGSPSFSG LRIVALTDGH 550 560 570 580 590 600 KGKTWGPSTM HQRERSLLPS QLSGGQPEWP AQTSTHSSFS KSAPNLDKKQ QQQNQQQVAS 610 620 630 640 650 660 LTPPPGLGIL GGSGGAGGTP ATPLLYPGIP IILTRPNNNN IGNCKAITTT ITTTTTTTTN 670 680 690 700 710 720 NNNNNNNSIS ANNNNQLNNI STINSNNNNN QTNLTSQPNT IIVLQNGRNN SNSSTTSQSP 730 740 750 760 770 780 AKIYHRARSQ EYGLDHPLAY QPPPLYLVTD DSSETDTVAS PTGCFHFLKS GNSSAASGAV 790 800 810 820 830 840 HLHRFGGSLG NSPAVGRKKH SLDSSSHHPP ANGSNSFALP NQLTLPSEDN NTYDHAFYRD 850 860 870 880 890 900 VIKKMSMASS ERVNSKSSGD LTMYNSSTPL TARDCDDAEE AFEGGRFQRN FSGSQFPRHC 910 920 930 940 950 960 FFTRQEEEGE AEDEDAVAAE VDTADADADD ECQVPASQMR QNSTTSRKSS VTFQSVSFEE 970 980 990 1000 1010 1020 PDFVATPRTT ARSDLYTSSA SISFATYRSA SPSLSSSSTT ASASPSIAST EAVNGYHMQE 1030 1040 1050 1060 1070 1080 NSILNTRRMQ DVQPHPDVIK LRAQEQRQQT KNQKKQRPKH ITKSKSVEAP VEGQHHEHDD 1090 1100 1110 1120 1130 1140 HNDPQHQHHS AGSSKIRALF NLFTRSRKKY SKLAEHNMVG GPEFCAIDPY QTDLAMGGSS 1150 1160 RSLKRKGKKP QTQSCEQLER C

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Activation of the JNK pathway during dorsal closure in Drosophila requires the mixed lineage kinase, slipper." Stronach B., Perrimon N. Genes Dev. 16:377-387(2002) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, DISRUPTION PHENOTYPE. Strain: Berkeley. Tissue: Head.
[2]	"The genome sequence of Drosophila melanogaster." Adams M.D., Celniker S.E., Holt R.A., Evans C.A., Gocayne J.D., Amanatides P.G., Scherer S.E., Li P.W., Hoskins R.A., Galle R.F., George R.A., Lewis S.E., Richards S., Ashburner M., Henderson S.N., Sutton G.G., Wortman J.R., Yandell M.D. , Zhang Q., Chen L.X., Brandon R.C., Rogers Y.-H.C., Blazej R.G., Champe M., Pfeiffer B.D., Wan K.H., Doyle C., Baxter E.G., Helt G., Nelson C.R., Miklos G.L.G., Abril J.F., Agbayani A., An H.-J., Andrews-Pfannkoch C., Baldwin D., Ballew R.M., Basu A., Baxendale J., Bayraktaroglu L., Beasley E.M., Beeson K.Y., Benos P.V., Berman B.P., Bhandari D., Bolshakov S., Borkova D., Botchan M.R., Bouck J., Brokstein P., Brottier P., Burtis K.C., Busam D.A., Butler H., Cadieu E., Center A., Chandra I., Cherry J.M., Cawley S., Dahlke C., Davenport L.B., Davies P., de Pablos B., Delcher A., Deng Z., Mays A.D., Dew I., Dietz S.M., Dodson K., Doup L.E., Downes M., Dugan-Rocha S., Dunkov B.C., Dunn P., Durbin K.J., Evangelista C.C., Ferraz C., Ferriera S., Fleischmann W., Fosler C., Gabrielian A.E., Garg N.S., Gelbart W.M., Glasser K., Glodek A., Gong F., Gorrell J.H., Gu Z., Guan P., Harris M., Harris N.L., Harvey D.A., Heiman T.J., Hernandez J.R., Houck J., Hostin D., Houston K.A., Howland T.J., Wei M.-H., Ibegwam C., Jalali M., Kalush F., Karpen G.H., Ke Z., Kennison J.A., Ketchum K.A., Kimmel B.E., Kodira C.D., Kraft C.L., Kravitz S., Kulp D., Lai Z., Lasko P., Lei Y., Levitsky A.A., Li J.H., Li Z., Liang Y., Lin X., Liu X., Mattei B., McIntosh T.C., McLeod M.P., McPherson D., Merkulov G., Milshina N.V., Mobarry C., Morris J., Moshrefi A., Mount S.M., Moy M., Murphy B., Murphy L., Muzny D.M., Nelson D.L., Nelson D.R., Nelson K.A., Nixon K., Nusskern D.R., Pacleb J.M., Palazzolo M., Pittman G.S., Pan S., Pollard J., Puri V., Reese M.G., Reinert K., Remington K., Saunders R.D.C., Scheeler F., Shen H., Shue B.C., Siden-Kiamos I., Simpson M., Skupski M.P., Smith T.J., Spier E., Spradling A.C., Stapleton M., Strong R., Sun E., Svirskas R., Tector C., Turner R., Venter E., Wang A.H., Wang X., Wang Z.-Y., Wassarman D.A., Weinstock G.M., Weissenbach J., Williams S.M., Woodage T., Worley K.C., Wu D., Yang S., Yao Q.A., Ye J., Yeh R.-F., Zaveri J.S., Zhan M., Zhang G., Zhao Q., Zheng L., Zheng X.H., Zhong F.N., Zhong W., Zhou X., Zhu S.C., Zhu X., Smith H.O., Gibbs R.A., Myers E.W., Rubin G.M., Venter J.C. Science 287:2185-2195(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. Strain: Berkeley.
[3]	"Annotation of the Drosophila melanogaster euchromatic genome: a systematic review." Misra S., Crosby M.A., Mungall C.J., Matthews B.B., Campbell K.S., Hradecky P., Huang Y., Kaminker J.S., Millburn G.H., Prochnik S.E., Smith C.D., Tupy J.L., Whitfield E.J., Bayraktaroglu L., Berman B.P., Bettencourt B.R., Celniker S.E., de Grey A.D.N.J. , Drysdale R.A., Harris N.L., Richter J., Russo S., Schroeder A.J., Shu S.Q., Stapleton M., Yamada C., Ashburner M., Gelbart W.M., Rubin G.M., Lewis S.E. Genome Biol. 3:RESEARCH0083.1-RESEARCH0083.22(2002) [PubMed] [Europe PMC] [Abstract] Cited for: GENOME REANNOTATION. Strain: Berkeley.
[4]	"A Drosophila full-length cDNA resource." Stapleton M., Carlson J.W., Brokstein P., Yu C., Champe M., George R.A., Guarin H., Kronmiller B., Pacleb J.M., Park S., Wan K.H., Rubin G.M., Celniker S.E. Genome Biol. 3:RESEARCH0080.1-RESEARCH0080.8(2002) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: Berkeley. Tissue: Head.
[5]	"Drosophila mixed lineage kinase/slipper, a missing biochemical link in Drosophila JNK signaling." Sathyanarayana P., Barthwal M.K., Lane M.E., Acevedo S.F., Skoulakis E.M., Bergmann A., Rana A. Biochim. Biophys. Acta 1640:77-84(2003) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 14-1161, FUNCTION, CATALYTIC ACTIVITY, TISSUE SPECIFICITY. Strain: Berkeley. Tissue: Embryo.
[6]	"Activation of the Drosophila MLK by ceramide reveals TNF-alpha and ceramide as agonists of mammalian MLK3." Sathyanarayana P., Barthwal M.K., Kundu C.N., Lane M.E., Bergmann A., Tzivion G., Rana A. Mol. Cell 10:1527-1533(2002) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, ENZYME REGULATION, MUTAGENESIS OF LYS-169.
[7]	"Phosphoproteome analysis of Drosophila melanogaster embryos." Zhai B., Villen J., Beausoleil S.A., Mintseris J., Gygi S.P. J. Proteome Res. 7:1675-1682(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-525 AND THR-862, MASS SPECTROMETRY. Tissue: Embryo.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AY045717 mRNA. Translation: AAK98795.1. AE014298 Genomic DNA. Translation: AAF46344.3. Sequence problems. AY119549 mRNA. Translation: AAM50203.1. AF416233 mRNA. Translation: AAL08011.1.
RefSeq	NP_001188559.1. NM_001201630.1. NP_001188560.1. NM_001201631.1. NP_572458.3. NM_132230.3.
3D structure databases
ProteinModelPortal	Q95UN8.
SMR	Q95UN8. Positions 58-466.
ModBase	Search...
Proteomic databases
PaxDb	Q95UN8.
PRIDE	Q95UN8.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
GeneID	44111.
KEGG	dme:Dmel_CG2272.
Organism-specific databases
CTD	44111.
FlyBase	FBgn0030018. slpr.
Phylogenomic databases
eggNOG	COG0515.
InParanoid	Q95UN8.
OrthoDB	EOG42JM6B.
Gene expression databases
Bgee	Q95UN8.
GermOnline	CG2272. Drosophila melanogaster.
Family and domain databases
InterPro	IPR011009. Kinase-like_dom. IPR015785. MAPKKK9/10/11-like. IPR000719. Prot_kinase_cat_dom. IPR001245. Ser-Thr/Tyr_kinase_cat_dom. IPR008271. Ser/Thr_kinase_AS. IPR001452. SH3_domain. [Graphical view]
PANTHER	PTHR23257:SF87. PTHR23257:SF87. 1 hit.
Pfam	PF07714. Pkinase_Tyr. 1 hit. PF00018. SH3_1. 1 hit. [Graphical view]
PRINTS	PR00452. SH3DOMAIN. PR00109. TYRKINASE.
SMART	SM00326. SH3. 1 hit. [Graphical view]
SUPFAM	SSF56112. Kinase_like. 1 hit. SSF50044. SH3. 1 hit.
PROSITE	PS00107. PROTEIN_KINASE_ATP. False negative. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. PS50002. SH3. 1 hit. [Graphical view]
ProtoNet	Search...
Other
GenomeRNAi	44111.
NextBio	836785.

Entry information

Entry name

M3KSL_DROME

Accession

Primary (citable) accession number: Q95UN8
Secondary accession number(s): Q8MRK7, Q95VF6, Q9W3I3

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 19, 2005
Last sequence update:	December 1, 2001
Last modified:	May 1, 2013
This is version 96 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Drosophila annotation project