Q3U1V8
SS
Gene name |
Map3k9 |
Protein name |
Mitogen-activated protein kinase kinase kinase 9 |
Names |
EC 2.7.11.25 |
Species |
Mus musculus (Mouse) |
KEGG Pathway |
mmu:338372 |
EC number |
2.7.11.25: Protein-serine/threonine kinases |
Protein Class |
|
Descriptions
Mixed lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase (MAPKKK) that activates the c-Jun N-terminal kinase (JNK) pathway through the dual phosphorylation of mitogen-activated protein kinase kinases 4/7 (MKK4/7). The catalytic domain of MLK3 is flanked by an N-terminal SH3 domain and a centrally located zipper and Cdc42/Rac-interactive binding (CRIB) motif. Zipper-mediated homo-oligomerization is required for full activity of MLK3, proper substrate phosphorylation, and activation of the JNK pathway. MLK3 is autoinhibited through an interaction between its SH3 domain and a proline-containing sequence between the zipper and the CRIB motif. Activated forms of the small GTPases Cdc42 and Rac interact with MLK3 in a CRIB motif-dependent manner to increase the autophosphorylation of MLK3 and substrate phosphorylation activity and to potentiate MLK3-induced activation of JNK. Activated Cdc42 translocates MLK3 to membranes and induces activation loop phosphorylation of MLK3.
Autoinhibitory domains (AIDs)
Target domain |
483-505 (Proline-rich region) |
Relief mechanism |
Partner binding |
Assay |
|
Accessory elements
286-307 (Activation loop from InterPro)
Target domain |
137-405 (Protein kinase domain) |
Relief mechanism |
|
Assay |
|
References
- Zhang H et al. (2001) "Autoinhibition of mixed lineage kinase 3 through its Src homology 3 domain", The Journal of biological chemistry, 276, 45598-603
- Du Y et al. (2005) "Cdc42 induces activation loop phosphorylation and membrane targeting of mixed lineage kinase 3", The Journal of biological chemistry, 280, 42984-93
- Handley ME et al. (2007) "Mixed lineage kinases (MLKs): a role in dendritic cells, inflammation and immunity", International journal of experimental pathology, 88, 111-26
- Kokoszka ME et al. (2018) "Identification of two distinct peptide-binding pockets in the SH3 domain of human mixed-lineage kinase 3", The Journal of biological chemistry, 293, 13553-13565
Autoinhibited structure
Activated structure
1 structures for Q3U1V8
| Entry ID | Method | Resolution | Chain | Position | Source |
|---|---|---|---|---|---|
| AF-Q3U1V8-F1 | Predicted | AlphaFoldDB |
47 variants for Q3U1V8
| Variant ID(s) | Position | Change | Description | Diseaes Association | Provenance |
|---|---|---|---|---|---|
| rs3389216290 | 91 | Q>R | No | EVA | |
| rs3389261878 | 129 | L>P | No | EVA | |
| rs3403600454 | 148 | F>L | No | EVA | |
| rs3389251049 | 170 | P>R | No | EVA | |
| rs3389245621 | 184 | E>K | No | EVA | |
| rs3389251079 | 189 | A>T | No | EVA | |
| rs3389256218 | 190 | M>I | No | EVA | |
| rs3389261933 | 198 | A>P | No | EVA | |
| rs3389256159 | 202 | V>L | No | EVA | |
| rs3389245464 | 204 | L>Q | No | EVA | |
| rs3389208861 | 207 | P>H | No | EVA | |
| rs3389222134 | 260 | R>* | No | EVA | |
| rs3389179920 | 350 | V>E | No | EVA | |
| rs3413134899 | 357 | N>T | No | EVA | |
| rs3389208800 | 370 | P>A | No | EVA | |
| rs3389256174 | 373 | K>R | No | EVA | |
| rs3389248845 | 413 | H>R | No | EVA | |
| rs3389248890 | 532 | R>G | No | EVA | |
| rs3389216248 | 536 | I>N | No | EVA | |
| rs3389222100 | 559 | P>T | No | EVA | |
| rs46926462 | 571 | V>I | No | EVA | |
| rs3389258085 | 576 | E>V | No | EVA | |
| rs3389261930 | 590 | R>L | No | EVA | |
| rs3403599286 | 625 | N>Y | No | EVA | |
| rs3389256182 | 637 | P>H | No | EVA | |
| rs3549527070 | 655 | S>N | No | EVA | |
| rs245720422 | 660 | Q>L | No | EVA | |
| rs3403618304 | 675 | R>H | No | EVA | |
| rs3389251075 | 699 | S>C | No | EVA | |
| rs3389233175 | 699 | S>N | No | EVA | |
| rs3389242946 | 712 | G>D | No | EVA | |
| rs3389179857 | 768 | F>Y | No | EVA | |
| rs3389242936 | 788 | K>E | No | EVA | |
| rs3389245582 | 817 | R>G | No | EVA | |
| rs3389222142 | 837 | V>L | No | EVA | |
| rs256811827 | 854 | R>Q | No | EVA | |
| rs3389245447 | 862 | P>L | No | EVA | |
| rs3389245659 | 863 | N>K | No | EVA | |
| rs3389258146 | 876 | P>T | No | EVA | |
| rs233684766 | 877 | T>M | No | EVA | |
| rs3389206655 | 899 | V>L | No | EVA | |
| rs3410290877 | 919 | L>F | No | EVA | |
| rs3389251108 | 926 | R>L | No | EVA | |
| rs3389261860 | 932 | P>S | No | EVA | |
| rs3549504885 | 989 | R>H | No | EVA | |
| rs262892853 | 1034 | L>P | No | EVA | |
| rs3389261864 | 1058 | R>K | No | EVA |
No associated diseases with Q3U1V8
10 regional properties for Q3U1V8
| Type | Name | Position | InterPro Accession |
|---|---|---|---|
| domain | Protein kinase domain | 137 - 405 | IPR000719 |
| domain | Serine-threonine/tyrosine-protein kinase, catalytic domain | 213 - 226 | IPR001245-1 |
| domain | Serine-threonine/tyrosine-protein kinase, catalytic domain | 251 - 269 | IPR001245-2 |
| domain | Serine-threonine/tyrosine-protein kinase, catalytic domain | 304 - 314 | IPR001245-3 |
| domain | Serine-threonine/tyrosine-protein kinase, catalytic domain | 323 - 345 | IPR001245-4 |
| domain | Serine-threonine/tyrosine-protein kinase, catalytic domain | 367 - 389 | IPR001245-5 |
| domain | SH3 domain | 45 - 109 | IPR001452 |
| active_site | Serine/threonine-protein kinase, active site | 257 - 269 | IPR008271 |
| binding_site | Protein kinase, ATP binding site | 143 - 164 | IPR017441 |
| domain | MLK1-3, SH3 domain | 49 - 106 | IPR035779 |
Functions
| Description | ||
|---|---|---|
| EC Number | 2.7.11.25 | Protein-serine/threonine kinases |
| Subcellular Localization |
|
|
| PANTHER Family | ||
| PANTHER Subfamily | ||
| PANTHER Protein Class | ||
| PANTHER Pathway Category | No pathway information available | |
1 GO annotations of cellular component
| Name | Definition |
|---|---|
| cytoplasm | The contents of a cell excluding the plasma membrane and nucleus, but including other subcellular structures. |
3 GO annotations of molecular function
| Name | Definition |
|---|---|
| ATP binding | Binding to ATP, adenosine 5'-triphosphate, a universally important coenzyme and enzyme regulator. |
| JUN kinase kinase kinase activity | Catalysis of the reaction |
| protein serine kinase activity | Catalysis of the reactions |
3 GO annotations of biological process
| Name | Definition |
|---|---|
| apoptotic process | A programmed cell death process which begins when a cell receives an internal (e.g. DNA damage) or external signal (e.g. an extracellular death ligand), and proceeds through a series of biochemical events (signaling pathway phase) which trigger an execution phase. The execution phase is the last step of an apoptotic process, and is typically characterized by rounding-up of the cell, retraction of pseudopodes, reduction of cellular volume (pyknosis), chromatin condensation, nuclear fragmentation (karyorrhexis), plasma membrane blebbing and fragmentation of the cell into apoptotic bodies. When the execution phase is completed, the cell has died. |
| phosphorylation | The process of introducing a phosphate group into a molecule, usually with the formation of a phosphoric ester, a phosphoric anhydride or a phosphoric amide. |
| positive regulation of apoptotic process | Any process that activates or increases the frequency, rate or extent of cell death by apoptotic process. |
41 homologous proteins in AiPD
| UniProt AC | Gene Name | Protein Name | Species | Evidence Code |
|---|---|---|---|---|
| A2VDU3 | MAP3K7 | Mitogen-activated protein kinase kinase kinase 7 | Bos taurus (Bovine) | SS |
| Q4TVR5 | DSTYK | Dual serine/threonine and tyrosine protein kinase | Bos taurus (Bovine) | PR |
| Q3SZJ2 | RIPK2 | Receptor-interacting serine/threonine-protein kinase 2 | Bos taurus (Bovine) | PR |
| Q6XUX0 | DSTYK | Dual serine/threonine and tyrosine protein kinase | Gallus gallus (Chicken) | PR |
| P83104 | Takl1 | Putative mitogen-activated protein kinase kinase kinase 7-like | Drosophila melanogaster (Fruit fly) | PR |
| Q95UN8 | slpr | Mitogen-activated protein kinase kinase kinase | Drosophila melanogaster (Fruit fly) | EV |
| O43353 | RIPK2 | Receptor-interacting serine/threonine-protein kinase 2 | Homo sapiens (Human) | PR |
| Q8NB16 | MLKL | Mixed lineage kinase domain-like protein | Homo sapiens (Human) | EV |
| P00540 | MOS | Proto-oncogene serine/threonine-protein kinase mos | Homo sapiens (Human) | PR |
| Q5TCX8 | MAP3K21 | Mitogen-activated protein kinase kinase kinase 21 | Homo sapiens (Human) | PR |
| Q6XUX3 | DSTYK | Dual serine/threonine and tyrosine protein kinase | Homo sapiens (Human) | PR |
| O43318 | MAP3K7 | Mitogen-activated protein kinase kinase kinase 7 | Homo sapiens (Human) | SS |
| Q9NYL2 | MAP3K20 | Mitogen-activated protein kinase kinase kinase 20 | Homo sapiens (Human) | PR |
| Q38SD2 | LRRK1 | Leucine-rich repeat serine/threonine-protein kinase 1 | Homo sapiens (Human) | EV |
| Q16584 | MAP3K11 | Mitogen-activated protein kinase kinase kinase 11 | Homo sapiens (Human) | EV |
| Q02779 | MAP3K10 | Mitogen-activated protein kinase kinase kinase 10 | Homo sapiens (Human) | SS |
| P80192 | MAP3K9 | Mitogen-activated protein kinase kinase kinase 9 | Homo sapiens (Human) | SS |
| Q62073 | Map3k7 | Mitogen-activated protein kinase kinase kinase 7 | Mus musculus (Mouse) | EV |
| P00536 | Mos | Proto-oncogene serine/threonine-protein kinase mos | Mus musculus (Mouse) | PR |
| P58801 | Ripk2 | Receptor-interacting serine/threonine-protein kinase 2 | Mus musculus (Mouse) | PR |
| Q66L42 | Map3k10 | Mitogen-activated protein kinase kinase kinase 10 | Mus musculus (Mouse) | SS |
| Q80XI6 | Map3k11 | Mitogen-activated protein kinase kinase kinase 11 | Mus musculus (Mouse) | PR |
| Q8VDG6 | Map3k21 | Mitogen-activated protein kinase kinase kinase 21 | Mus musculus (Mouse) | PR |
| P04627 | Araf | Serine/threonine-protein kinase A-Raf | Mus musculus (Mouse) | PR |
| O55222 | Ilk | Integrin-linked protein kinase | Mus musculus (Mouse) | PR |
| Q9ESL4 | Map3k20 | Mitogen-activated protein kinase kinase kinase 20 | Mus musculus (Mouse) | PR |
| Q99N57 | Raf1 | RAF proto-oncogene serine/threonine-protein kinase | Mus musculus (Mouse) | SS |
| P28028 | Braf | Serine/threonine-protein kinase B-raf | Mus musculus (Mouse) | SS |
| Q9D2Y4 | Mlkl | Mixed lineage kinase domain-like protein | Mus musculus (Mouse) | SS |
| P0C8E4 | Map3k7 | Mitogen-activated protein kinase kinase kinase 7 | Rattus norvegicus (Rat) | SS |
| D3ZG83 | Map3k10 | Mitogen-activated protein kinase kinase kinase 10 | Rattus norvegicus (Rat) | SS |
| P00539 | Mos | Proto-oncogene serine/threonine-protein kinase mos | Rattus norvegicus (Rat) | PR |
| Q66HA1 | Map3k11 | Mitogen-activated protein kinase kinase kinase 11 | Rattus norvegicus (Rat) | PR |
| Q9TZM3 | lrk-1 | Leucine-rich repeat serine/threonine-protein kinase 1 | Caenorhabditis elegans | SS |
| Q9FPR3 | EDR1 | Serine/threonine-protein kinase EDR1 | Arabidopsis thaliana (Mouse-ear cress) | PR |
| Q2MHE4 | HT1 | Serine/threonine/tyrosine-protein kinase HT1 | Arabidopsis thaliana (Mouse-ear cress) | PR |
| O22558 | STY8 | Serine/threonine-protein kinase STY8 | Arabidopsis thaliana (Mouse-ear cress) | PR |
| Q8RWL6 | STY17 | Serine/threonine-protein kinase STY17 | Arabidopsis thaliana (Mouse-ear cress) | PR |
| F4JTP5 | STY46 | Serine/threonine-protein kinase STY46 | Arabidopsis thaliana (Mouse-ear cress) | PR |
| Q05609 | CTR1 | Serine/threonine-protein kinase CTR1 | Arabidopsis thaliana (Mouse-ear cress) | PR |
| Q67E00 | dstyk | Dual serine/threonine and tyrosine protein kinase | Xenopus tropicalis (Western clawed frog) (Silurana tropicalis) | PR |
| 10 | 20 | 30 | 40 | 50 | 60 |
| MESSRSLLGC | LASATAAPPG | DDATGAGAEE | EEDEEEAAAE | LGSHAALPYW | TAVFEYEAAG |
| 70 | 80 | 90 | 100 | 110 | 120 |
| EDELTLRLGD | VVEVLSKDSQ | VSGDEGWWTG | QLNQRVGIFP | SNYVTPRSAF | SSRCQPGAED |
| 130 | 140 | 150 | 160 | 170 | 180 |
| PSCYPPIQLL | EIDFAELTLE | EIIGIGGFGK | VYRAFWAGDE | VAVKAARHDP | DEDISQTIEN |
| 190 | 200 | 210 | 220 | 230 | 240 |
| VRQEAKLFAM | LKHPNIIALR | GVCLKEPNLC | LVMEFARGGP | LNRVLSGKRI | PPDILVNWAV |
| 250 | 260 | 270 | 280 | 290 | 300 |
| QIARGMNYLH | DEAIVPIIHR | DLKSSNILIL | QKVENGDLSN | KILKITDFGL | AREWHRTTKM |
| 310 | 320 | 330 | 340 | 350 | 360 |
| SAAGTYAWMA | PEVIRASMFS | KGSDVWSYGV | LLWELLTGEV | PFRGIDGLAV | AYGVAMNKLA |
| 370 | 380 | 390 | 400 | 410 | 420 |
| LPIPSTCPEP | FAKLMEDCWN | PDPHSRPSFT | SILDQLTTIE | ESGFFEMPKD | SFHCLQDDWK |
| 430 | 440 | 450 | 460 | 470 | 480 |
| HEIQEMFDQL | RAKEKELRTW | EEELTRAALQ | QKNQEELLRR | REQELAEREI | DILERELNII |
| 490 | 500 | 510 | 520 | 530 | 540 |
| IHQLCQEKPR | VKKRKGKFRK | SRLKLKDGNR | ISLPSDFQHK | FTVQASPTMD | KRKSLISNRS |
| 550 | 560 | 570 | 580 | 590 | 600 |
| SPPASPTIIP | RLRAIQLTPG | ESSKTWGRSS | VVPKEEGEEE | EKRAPKKKGR | TWGPGTLGQK |
| 610 | 620 | 630 | 640 | 650 | 660 |
| ELTSGDEGLK | SLVDGYKQWS | SSAPNLGKGP | RSSPALPGFT | SLMEIEDEDS | EGPGSGENHQ |
| 670 | 680 | 690 | 700 | 710 | 720 |
| QHSPNQSYLC | IPFPRGEDGD | GPSSDGVHEE | PTPVNSATST | PQLTPTNSLK | RGGTHHRRCE |
| 730 | 740 | 750 | 760 | 770 | 780 |
| VALLGCGAVL | AATGLGFDLL | EAGKCQLLPP | EEPEPPAREE | KKRREGLFQR | ASRPRRSTSP |
| 790 | 800 | 810 | 820 | 830 | 840 |
| PSRKLFKKEE | PMTLLGDPSA | SLTLLSLSSI | SECNSTRSLL | RSDSDEIVVY | EMPVSPVEAP |
| 850 | 860 | 870 | 880 | 890 | 900 |
| PLTQCTHNPL | VNVRVERFKR | DPNQSLTPTH | VTLTAPTQPS | GHRRTPSDGA | LKPTAAPAVL |
| 910 | 920 | 930 | 940 | 950 | 960 |
| GSRSPSSNGM | SPSPGTGMLK | TPSPSRDPGE | FPRLPDPNVV | FPPTPRRWNT | QRDSTLERPK |
| 970 | 980 | 990 | 1000 | 1010 | 1020 |
| TLEFLPRPRP | SANRQRLDPW | WFVSPSHARS | ASPANSSSTE | TPSNLDSCFA | SSSSTVEERP |
| 1030 | 1040 | 1050 | 1060 | 1070 | |
| GLPALLPLQA | GPLLPAERTL | LDLDAEGQSQ | DSTVPLCRAE | LNAHGPSPYE | IQQEFWS |