TABLE 1.
Summary of JNK substratesa
| Protein functional group and nameb | Function | No. of JNK target phospho-sitesc | D-motif typec | Suppl. table(s) | Reference(s) |
|---|---|---|---|---|---|
| 1. Transcription, DNA and chromatin regulation | |||||
| ATF2# | Transcription factor | 2 | B | S3 | 164, 230 |
| Beta-catenin | Transcriptional coactivator | 2 (+2) | D | S5, S6 | 270, 272, 471 |
| c-Jun# | Transcription factor | 4 | B | S3 | 224, 229 |
| Cdt1 | DNA replication factor | 3 | D | S5 | 252 |
| Elk1# | Transcription factor | 2 | A | S3 | 472, 473 |
| Elk3 | Transcription factor | 4 | C | S4 | 343 |
| Elk4 | Transcription factor | 6 | C | S4 | 474 |
| FOXO3 | Transcription factor | 1 | D | S5 | 236 |
| FOXO4 | Transcription factor | 2 | D | S5 | 235 |
| Gli1 | Transcription factor | 1 | C | S4 | 69 |
| Gli3 | Transcription factor | 1 | C | S4 | 69 |
| Hes1† | Transcription factor | 1 | D | S5 | 232 |
| HSF1‡ | Transcription factor | 1 | B | S3 | 316 |
| JDP2# | Transcription factor | 1 | D | S5 | 475 |
| JunD# | Transcription factor | 3 | B | S3 | 476 |
| Myc# | Transcription factor | 2 | D | S5 | 231 |
| NFAT1 (NFATc2) | Transcription factor | 2 | D | S5 | 309 |
| NFAT2 (NFATc1)‡ | Transcription factor | 1 | D | S5 | 308 |
| NFAT4† | Transcription factor | 2 | B | S3 | 307 |
| NF-E2 | Transcription factor | 1 (+1) | D | S5, S6 | 471 |
| Nrl# | Transcription factor | 1 | D | S5 | 347 |
| p53 | Transcription factor | 1 | D | S5 | 238 |
| p73† | Transcription factor | 6 | D | S5 | 239 |
| RRN3 (TIF1A) | Transcription factor | 1 | D | S5 | 477 |
| Sirtuin | Histone deacetylase | 1 (+1) | D | S5, S6 | 253, 254 |
| Smad2# | Transcription factor | 2 | D | S5 | 478, 479 |
| Smad3# | Transcription factor | 2 | D | S5 | 478, 479 |
| Sp1† | Transcription factor | 2 | D | S5 | 234 |
| STAT1 | Transcription factor | 1 | D | S5 | 480 |
| STAT3 | Transcription factor | 1 | D | S5 | 481 |
| Twist1† | Transcription factor | 1 | D | S5 | 233 |
| YAP1† | Transcriptional coactivator | 4 | D | S5 | 246 |
| POU6F1 (TCF-β1) | Transcription factor | (2) | D | S6 | 482 |
| Histone H3.1 | Histone (DNA packaging) | (1) | D | S6 | 483 |
| Runx2 | Transcription factor | (1) | D | S6 | 484 |
| 2. mRNA splicing and translation | |||||
| DCP1a | mRNA decapping enzyme | 1 | D | S5 | 255 |
| eEF1α2 | Elongation factor | 1 (+1) | D | S5, S6 | 259 |
| hnRNPK† | RNA-binding protein | 3 | C | S4 | 256 |
| SP45 | RNA-splicing factor | 1 | D | S5 | 258 |
| AIMP1 | tRNA synthase regulator | (1) | D | S6 | 485 |
| 3. Receptors and sensors | |||||
| Androgen receptor† | Nuclear hormone receptor | 1 | D | S5 | 240 |
| Glucocorticoid receptor† | Nuclear hormone receptor | 1 | D | S5 | 241 |
| GluR2† | Receptor ion channel | 1 | D | S5 | 288 |
| GluR4† | Receptor ion channel | 1 | D | S5 | 288 |
| LRP6 | Wnt coreceptor | 1 | D | S5 | 486 |
| LSR (angulin) | Lipoprotein receptor | 1 | D | S5 | 487 |
| Nur77# | Nuclear hormone receptor | 1 | D | S5 | 488 |
| PPAR㇠| Nuclear hormone receptor | 1 | D | S5 | 242 |
| RARα# | Nuclear hormone receptor | 3 | D | S5 | 243 |
| RXRαd* | Nuclear hormone receptor | 4 | D | S5 | 244, 245 |
| SREBP1 | Lipid sensor | 2 | D | S5 | 489 |
| 4. Protein phosphorylation and dephosphorylation | |||||
| Akt1 | Protein kinase | 1 | D | S5 | 490 |
| DLK | Protein kinase | 4 (+1) | D | S5, S6 | 44 |
| DUSP8 (M3/6) | Protein phosphatase | 3 | D | S5 | 491 |
| S6K (p70RSK)# | Protein kinase | 2 | D | S5 | 333 |
| PPM1J# | Protein phosphatase | 3 | A | S3 | 69, 71 |
| Cdc25B | Protein phosphatase | 2 | D | S5 | 492, 493 |
| Cdc25C | Protein phosphatase | 1 | D | S5 | 494, 495 |
| Raptor | Protein kinase regulator | 3 | D | S5 | 496 |
| 14-3-3-ζ* | Phospho-protein adaptor | 1 | D | S5 | 285, 359 |
| 14-3-3-σ* | Phospho-protein adaptor | 1 | D | S5 | 285 |
| MST1 | Protein kinase | (1) | D | S6 | 497 |
| RSK | Protein kinase | (1) | D | S6 | 498 |
| 5. Diverse scaffolds and adaptors | |||||
| DLG4 (PSD-95)† | Synaptic scaffold protein | 1 | D | S5 | 287 |
| eIF4ET | Nucleopore shuttling protein | 6 | D | S5 | 499 |
| IRS1† | Receptor-associated scaffold | 1 | A | S3 | 273 |
| IRS2† | Receptor-associated scaffold | 1 | A | S3 | 274 |
| Paxillin# | Cell adhesion receptor and cytoskeletal protein | 1 | D | S5 | 268, 269 |
| Shc1 | Receptor-associated scaffold | 1 | D | S5 | 500 |
| LIMD1 | Multipurpose adaptor | (2) | D | S6 | 501 |
| 6. Other signaling systems | |||||
| cPLA2 | Phospholipase | 1 | D | S5 | 502 |
| DAT1 (SLC6A3) | Dopamine transporter | 1 | D | S5 | 503 |
| eNOS* | Nitric oxide synthase | 1 | D | S5 | 358 |
| ITCH‡ | E3 ubiquitin ligase | 2 | D | S5 | 319, 504 |
| Rad18 | E3 ubiquitin ligase | 1 | D | S5 | 250 |
| Aquaporin-2 | Water channel | (1) | D | S6 | 505 |
| CDKN1B (p27Kip1) | Cyclin/Cdk inhibitor | (1) | D | S6 | 506 |
| (SMPD2) | Sphingomyelin phosphodiesterase | (1) | D | S6 | 507 |
| 7. Cytoskeletal proteins | |||||
| Cytokeratin-8‡ | Cytoskeletal protein | 1 | D | S5 | 310 |
| DCX† | Microtubule-associated protein | 3 | B | S3 | 260 – 262 |
| MAP2† | Microtubule-associated protein | 3 | D | S5 | 264 |
| MARCKSL1† | Actin-binding protein | 3 | D | S5 | 266 |
| SMTL2# | Actin-binding protein | 4 | A | S3 | 267 |
| Stathmin 1 | Microtubule-associated protein | 2 | C | S4 | 508 |
| Stathmin 2 (SCG10)# | Microtubule-associated protein | 2 | C | S4 | 509 |
| Taue# | Microtubule-associated protein | 3 | D | S5 | 265 |
| WDR62† | Microtubule-associated protein | 3 | B | S3 | 213 |
| KIF5C (kinesin) | Motor protein | 1 | D | S6 | 510 |
| Moesin | Cytoskeletal anchor protein | (1) | D | S6 | 511 |
| Stathmin 3 (SCLIP) | Microtubule-associated protein | (1) | D | S6 | 508 |
| 8. Vesicular transport | |||||
| APLP2 | Vesicular transport receptor | 1 | D | S5 | 217, 512 |
| β-APP# | Vesicular transport receptor | 1 | D | S5 | 217 |
| JIP1† | Vesicular transport adaptor | 7 | A | S3 | 104 |
| JIP3† | Vesicular transport adaptor | 3 | A | S3 | 275 |
| Synaptotagmin 4 | Vesicle fusion protein | 1 | D | S5 | 513 |
| 9. Mitochondrial control of apoptosis | |||||
| Bad‡ | BH3 only protein | 1 | D | S5 | 303 |
| Bax | Mitochondrial pore regulator | 1 | D | S5 | 514 |
| Bcl2‡ | Mitochondrial pore regulator | 3 | D | S5 | 305 |
| Bim‡ | BH3-only protein | 3 | D | S5 | 302 |
| Mcl1 | Mitochondrial pore regulator | 2 | A | S3 | 281 |
| Noxa (PMAIP) | BH3-only protein | 1 | D | S5 | 515 |
| Bid | BH3 motif protein | (1) | D | S6 | 516 |
| SMAC (Diablo) | Ubiquitin ligase inhibitor | (1) | D | S6 | 517 |
| 10. Unknown | |||||
| Sab (SH3BP5) | Mitochondrial, possible scaffold | 1 | A | S3 | 378, 518 |
The table presents JNK substrate proteins (104 in total; 89 well-validated JNK substrates [indicated in regular font] and 15 less-well-validated JNK substrates [indicated in italics]), listed alphabetically within each of the 10 major functional groupings (see Fig. S1 in the supplemental material for representations of these groupings for the 89 comprehensively and well-validated proteins). In addition to protein function, the number of characterized JNK target phosphorylation sites (again with well-validated information indicated in regular font and less-well-validated values indicated in italics) and the D-motif type are presented (this information represents a summary of the more-detailed information presented in Tables S3 to S6 in the supplemental material). Of these substrates, features of the interaction site with JNK have been defined for 23 protein substrates: 9 with a JIP1-like site (class A), 7 with an NFAT-like site (class B), and 7 with a weak, incomplete, or atypical binding sequence (class C). Class D sites are uncharacterized. The ratios of known JNK target sites per protein are 1.98 for all well-validated JNK substrates (i.e., 176 sites in 89 proteins), 2.70 for well-validated protein substrates possessing a known JNK-binding D-motif (i.e., 62 sites in 23 proteins), and only 1.73 for the well-validated protein substrates devoid of known D-motifs (i.e., 114 sites in 66 proteins).
Commonly used protein names and/or their commonly used acronyms are listed; when a protein is well known by >1 name, the alternative is presented in parentheses. Within a framework of understanding the immediate molecular consequences of JNK-mediated phosphorylation of these substrates, the following symbols indicate the impact of the indicated protein: ‡, negative phospho-switch (i.e., phosphorylation to negatively regulate protein-protein interactions or intramolecular interactions); #, positive phospho-switch (i.e., phosphorylation to positively regulate protein-protein interactions or intramolecular interactions); *, allosteric phospho-switch; †, a less-understood impact, including complex changes such as impacts on intracellular localization, as discussed in the text.
The total number of validated JNK target sites is indicated (additional possible sites are indicated in italics and parentheses). See the indicated table(s) in the supplemental material for further information (and also on D-motif classification, where indicated).
In addition, RXRα can be subjected to more complex regulation (245).