The DOI matches its Crossref record; 46 of the 46 references it cites were found in a registry or an index; none of the 25 sources its claims cite is checked for support yet.
Structural basis for the selective inhibition of JNK1 by the scaffolding protein JIP1 and SP600125
Open accessAbstract
The c-jun N-terminal kinase (JNK) signaling pathway is regulated by JNK-interacting protein-1 (JIP1), which is a scaffolding protein assembling the components of the JNK cascade. Overexpression of JIP1 deactivates the JNK pathway selectively by cytoplasmic retention of JNK and thereby inhibits gene expression mediated by JNK, which occurs in the nucleus. Here, we report the crystal structure of human JNK1 complexed with pepJIP1, the peptide fragment of JIP1, revealing its selectivity for JNK1 over other MAPKs and the allosteric inhibition mechanism. The van der Waals contacts by the three residues (Pro157, Leu160, and Leu162) of pepJIP1 and the hydrogen bonding between Glu329 of JNK1 and Arg156 of pepJIP1 are critical for the selective binding. Binding of the peptide also induces a hinge motion between the N- and C-terminal domains of JNK1 and distorts the ATP-binding cleft, reducing the affinity of the kinase for ATP. In addition, we also determined the ternary complex structure of pepJIP1-bound JNK1 complexed with SP600125, an ATP-competitive inhibitor of JNK, providing the basis for the JNK specificity of the compound.
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30 Own result · 26 Own interpretation · 20 Not checked yet · 3 No basis given · 1 Own method
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“Binding of the peptide also induces a hinge motion between the Nand C-terminal domains of JNK1”
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“Despite the small size of SP600125 (molecular weight ¼ 220), it effectively occupies the hydrophobic pocket of the ATP-binding site in JNK1”
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“As a result of the high homology of sequences with 92% identity, the overall architecture of JNK1 is substantially equal to that of JNK3 (PDB entry 1JNK; Xie et al , 1998).”
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- Not checked yetcites Xie et al , 1998 source
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“we have determined the crystal structure of JNK1 in complex with pepJIP1, the docking site peptide of JIP1 (residues 153-163), at a resolution of 2.35 A ˚ .”
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“and distorts the ATPbinding cleft”
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“Leu160 and Leu162 of the f A-Xf B motif in pepJIP1 are extensively surrounded by many hydrophobic residues of JNK1 including Met121, Val118, Leu115, Ala113, Leu123, Val59, Leu131, and Cys163”
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“Arg156 ( f A 4) interacts with Glu329 with a bidentate salt bridge of length 2.70 A ˚ .”
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“We also determined the structure of the ternary complex JNK1-pepJIP1-SP600125 at a resolution of 2.7 A ˚ .”
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“reducing the affinity of the kinase for ATP.”
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“It is the first structure demonstrating the way by which MAPKs are selectively regulated by their scaffolding proteins.”
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“the overall conformations and binding positions of the bound peptides are quite different from each other when the structures of JNK1 and p38 are superimposed”
What the sources say
- Not checked yetcites Chang et al , 2002 source
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“it is shown that the conformations in the f A-Xf B motifs are conserved”
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“The ordered phosphorylation loop in the structure of JNK3 partially blocks the substratebinding site.”
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“the similar increased disorder of the phosphorylation loop of p38 MAPK was also found when MEF2A or MKK3b peptide binds (Chang et al , 2002).”
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- Not checked yetcites Chang et al , 2002 source
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“a mutated pepJIP1, where the four key residues for interaction (R156, P157, L160, and L162) are replaced with alanine, does not inhibit the JNK1 activity due to the failure of binding to JNK1”
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“A close-up look at the catalytic cleft shows that the ATP-binding site is distorted on binding of pepJIP1 to JNK1”
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“In addition, SP600125 is surrounded by hydrophobic residues in the adenine-binding pocket (Ile32, Val40, Ala53, Ile86, Met108, Leu110, Val158, and Leu168) with effective van der Waals contacts”
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“The K d value was increased by three times when pepJIP1 is bound to JNK1 ( K d ¼ 55 7 16 m M) compared to free JNK1 ( K d ¼ 19 7 4.2 m M)”
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“We have also observed that pepJIP1 inhibits JNK1 to phosphorylate myelin basic protein (MBP), which is a substrate not containing a docking site, and that this inhibition is dosedependent.”
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“SP600125 exhibited selectivity against protein kinases including p38, ERK2, MKK1, GSK3 b , CSK, CK2, LCK, PDK1, PKB a , and PKA.”
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“The structural analysis in this study demonstrates that the peptide derived from the docking site of the scaffolding protein also binds at the same docking grooves of JNK1 as those of the upstream kinase and the substrate transcription factor do in p38 MAPK.”
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“when the full structures of combined Nand C-terminal domains are superimposed, the r.m.s. deviation for C a atoms runs to 3.84 A ˚ , indicating an extensive hinge motion between the two domains.”
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“Mutation of M108T or M108Q caused the complete removal of inhibition by SP600125 (Figure 7B and C).”
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“In the ternary complex structure, SP600125 makes two hydrogen bonds with JNK1 between the N atom at the 1-position and the backbone amide group of Met111, and between the NH group at the 2-position and the backbone carbonyl oxygen atom of Glu109 (Figure 7A).”
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“The distinct variations of amino acids are found at the amino acids corresponding to Met108 and Leu168 of JNK1.”
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“Surprisingly, the difference electron density corresponding to SP600125 clearly appeared on the adenine-binding pocket of the ATP-binding site (Figure 6).”
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“In this structure, a little shift of SP600125 from the position of the inhibitor bound to JNK3 was found as a result of the movement of the residues in the hydrophobic pocket (Figure 6D).”
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“and the variations of the crucial hydrophobic residues in other MAP kinases give SP600125 the JNK specificity.”
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“implying an allosteric inhibition mechanism of pepJIP1.”
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“demonstrating that Arg127 and Glu329 of JNK1 are key residues for pepJIP1 binding.”
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“This peptide, pepJIP1 (a peptide version of JIP1), inhibited JNK activity in vitro toward recombinant c-jun, Elk, and ATF2 up to 90% with significant selectivity of no inhibition of the related Erk and p38 MAPKs.”
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“any conformational change inside of the f A-Xf B motif may decrease the hydrophobic interactions of the two key residues, f A and f B, with the docking grooves of MAPKs, therefore inducing failure in the effective binding of docking sites to MAPKs.”
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“This inherent structural flexibility may play a central role in allowing the JNK pathway to be regulated by specific interactions with many docking site proteins.”
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“This result is very consistent with the previous structure-activity relationship studies, which revealed that all of the derivatives having N-alkyl substituents instead of the free NH group at the 2-position showed significant loss in inhibitory activity (Bennett et al , 2001).”
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- Not checked yetcites Bennett et al , 2001 source
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“implying that the number and position of basic residues in the docking sites are important determinants of specificity.”
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“A similar structural distortion of the ATP-binding site has been reported in the crystal structure of CDK6 bound to the tumor suppressor p16 INK4a or p19 INK4d (Brotherton et al , 1998; Russo et al , 1998).”
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“Although we could not get other crystals of unrelated lattices, this hinge motion is not likely to be a packing artifact because this structural feature is consistent with the experimental results including ITC measurement of ATP binding affinity and the inhibition of phosphorylation of a docking site-independent substrate by pepJIP1.”
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“The ability of JNK to bind different proteins including upstream kinases, substrate transcription factors, and scaffolding proteins with high specificity may be mediated by the conformational flexibility of the loop connecting b 7 and b 8 and the disordered 331-351 loop.”
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“the binding between JNK and pepJIP1 is not dependent on the kinase activity of JNK (Barr et al , 2002)”
What the sources say
- Not checked yetcites Barr et al , 2002 source
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“whereby the binding of SP600125 could not be influenced much by the distortion of the ATP-binding site, which moved the residues of JNK1 interacting with the phosphate groups of ATP far away from the active site (Figure 4B).”
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“This structural feature of JNK3 suggests that refolding of this loop is required to relieve steric constraints to the substrate binding and the activation of the substrate by JNK3 (Xie et al , 1998).”
What the sources say
- Not checked yetcites Xie et al , 1998 source
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“and the JNK specificity of SP600125 seems to come from the interactions with these hydrophobic residues.”
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- Rests on an assumption: SP600125 has similar potency against the JNK1, JNK2, and JNK3 isoforms.
- Rests on an assumption: The hydrophobic residues in the adenine-binding pocket are conserved across JNK isoforms.
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“In conclusion, the two major differences, the structural difference in a 2 helix and the involvement of the CD domain in docking interaction, provide the rationale for the predominant selectivity of pepJIP1 in inhibition of JNK, but not the related Erk or p38 MAPKs.”
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“It is thought that the selectivity of SP600125 may be determined by the size of the hydrophobic pocket, which varies in diverse protein kinases, and not merely by the amino acids themselves of the hydrophobic pocket.”
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“the variation in the amino acids corresponding to Met108 may lead us to the conclusion that the hydrophilic residues such as threonine or glutamine could repel the aromatic ring of SP600125 and thus reduce the inhibitory potency”
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“the distinct interaction between Glu329 of JNK1 and Arg156 of JIP1 shows the importance of the CD domain for the selective binding of a specific docking site.”
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“Inhibition of JNK1 by pepJIP1 is mainly due to the competition of pepJIP1 with other docking sites of the substrates or the upstream kinases (Dickens et al , 1997; Ho et al , 2003).”
What the sources say
- Not checked yetcites Dickens et al , 1997 source
- Not checked yetcites Ho et al , 2003
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“the similar mode of interaction is expected when pepJIP1 would bind to the active JNK1.”
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“The aromatic side chain of phenylalanine at Met108 position could interact with the aromatic ring of SP600125 by a T-shaped interaction.”
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“The structure of this ternary complex can be considered as a structural model for the state where SP600125 blocks JNK1 when it is bound to JIP1 scaffolding protein in vivo .”
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In the paper
“The K d values for pepJIP1 to bind to wild type, R127A, and E329A were found to be 0.42 7 0.13, 6.4 7 2.2, and 9.1 7 3.4 m M, respectively”
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“The peptide docks to the docking groove of JNK1, a surface of the Cterminal domain covering a 2, a 3, a 13, and b 8, which is away from the ATP pocket or substrate recognition site”
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“In this structure, it is found that the docking site of the scaffolding protein also binds at the same docking grooves of JNK1 as the upstream kinase and the substrate transcription factor do in p38 MAPK (Chang et al , 2002), but with quite different interaction modes.”
What the sources say
- Not checked yetcites Chang et al , 2002 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Much more residues of the phosphorylation loop of the JNK1 complex are disordered than the JNK3 structure (missing residues 175-187 in JNK1-pepJIP1 and 212-216 in JNK3) although their ordered regions adopt a similar conformation”
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The most interesting result of the pepJIP1 binding to JNK1 is the rotation of the N-terminal domain relative to the Cterminal domain by approximately 15 1 , thereby distorting the ATP-binding site and inducing disorder of the phosphorylation loop”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The most striking feature of the present structure is the distortion of the ATP-binding site induced by the interdomain rearrangement upon pepJIP1 binding, providing another mechanism of allosteric inhibition of the kinase activity by interfering with productive binding of ATP.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The hinge motion is triggered in b 8, which interacts with Leu162 ( f B) by van der Waals contacts, and is propagated to the N-terminal domain via the single loop, which connects b 7 and b 8.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Fortunately, the small molecule, SP600125, occupied the deepest adenine-binding site only, not expanding to the phosphate-binding site”
boostedSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The most notable difference is that the f A-Xf B motif of pepJIP1, especially Leu162 ( f B), is shifted by the structural difference between JNK1 and p38 in the region containing the hydrophobic residues critical for the f A-Xf B motif binding. In this region, JNK1 forms a oneturn helix ( a 2), but a two-turn helix in p38.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“in the structure of the JNK1-pepJIP1 complex, the a 1 helix moved too far away for such interactions to occur as a result of the interdomain rearrangement upon pepJIP1 binding, and this loss of interactions released the phosphorylation loop of JNK1pepJIP1 from the N-terminal domain, resulting in the increased disorder of the loop.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The root-mean-square (r.m.s.) deviations for C a atoms of the Nand C-terminal domain between the structures of JNK1-pepJIP1 and JNK3 are 1.27 and 0.79 A ˚ , respectively. These values show that there is no significant structural difference between the corresponding domains.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“However, the overexpression of either the domain within JIP1 that binds to JNK, or the full-length protein, potently inhibits JNK signaling in the cell (Dickens et al , 1997).”
What the sources say
- Not checked yetcites Dickens et al , 1997 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“JNK-interacting protein-1 (JIP1) was identified as a scaffolding protein of the JNK module in yeast two-hybrid analysis, enhancing the correspondent signaling through the pathway (Whitmarsh et al , 1998).”
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In the structure, the INK4 inhibitors bind next to the ATP-binding site, opposite where the activating cyclin binds, and thereby not only prevent cyclin binding indirectly but also reduce the affinity of the kinase for ATP by causing extensive allosteric changes in CDK6.”
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“This implies that JNK and p38 may act as chemomechanical energy transducers, using peptide binding energy to generate allosteric conformational changes (Goldsmith, 1996).”
What the sources say
- Not checked yetcites Goldsmith, 1996 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, similar but nonidentical docking grooves in each MAPKs appear to be the important determinant of pathway specificity in addition to the variations in sequences of docking sites.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“And the size of the pocket may also be connected with the intrinsic flexibility of the loops around the catalytic cleft in protein kinases, and the diverse modes of the flexibility dependent on each protein kinases could be important determinants of the selectivity of SP600125.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“SP600125 is a reversible ATPcompetitive inhibitor with more than 20-fold selectivity over other kinases including Erk, p38 MAPKs, MKKs, and PKCs.”
What the sources say
- Not checked yetcites Bennett et al , 2001 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Recently, the structure of JNK3 in complex with SP600125 was reported (PDB entry 1PMV; Scapin et al , 2003).”
What the sources say
- Not checked yetcites Scapin et al , 2003 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“In cells, SP600125 dose-dependently inhibited the phosphorylation of c-jun, the expression of inflammatory genes COX-2, IL2, IHNg , and TNFa , and prevented the activation and differentiation of human CD4 cell.”
What the sources say
- Not checked yetcites Bennett et al , 2001 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The latest result demonstrates that the JNK specificity of SP600125 is not so excellent and this compound inhibits some protein kinases with similar or greater potency than JNK (Bain et al , 2003).”
What the sources say
- Not checked yetcites Bain et al , 2003 source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This distortion would not eliminate the ATP binding, but it would significantly reduce ATP affinity and may well disorient any bound ATP with respect to the kinase catalysis, and thus inhibit the JNK activity to phosphorylate the substrates.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the release of the phosphorylation loop, when JNK binds to the JIP1 scaffolding protein, may give a chance for the loop to refold and take an appropriate conformation to be recognized and phosphorylated by MKKs, which are also scaffolded in JIP1, and be ready to recognize the substrates.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the docking site can be characterized by not only the sequential similarity of the f A-Xf B motifs but also the conformational conservation of the motifs in their structures.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In in vivo studies in mice, SP600125 inhibited lipopolysaccharide-induced expression of TNFa and prevented anti-CD3-mediated thymocyte apoptosis (Bennett et al , 2001).”
What the sources say
- Not checked yetcites Bennett et al , 2001 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In other words, the inhibition of the full-length JIP1 in vivo is more complicated than that of pepJIP1, and the structural feature of the inhibition by full-length JIP1 might have significant differences from that of pepJIP1.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The docking groove of JNK1 is expected to accommodate the docking sites of MKK7 or c-jun as that of p38 does, but there may exist other important determinants than the interaction by Arg156 ( f A 4) of JIP1 for specific recognition of the docking sites of MKK7 or c-jun because this residue is not conserved in the sequential comparison (Figure 1D).”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Phosphorylation of JNK by MKKs and activation of c-jun by JNK also might undergo such an interdomain rearrangement as the JNK1-pepJIP1 complex due to the intrinsic flexibility of the loops around the catalytic cleft.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These previous studies imply that therapeutic inhibition of JNK has significant potential in inflammatory disease, acute organ failure due to apoptotic cell death, and cancer.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The fact that the N- and C-terminal domains are linked by only two loops, the loop connecting b 7 and b 8 and the disordered 331-351 loop, implies that the intrinsic flexibility may exist in the kinase, and the inherent structural flexibility may play a central role in its regulation upon JIP1 binding to JNK1.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
SP600125 has similar potency against the JNK1, JNK2, and JNK3 isoforms.
“SP600125 inhibited JNK1, 2, and 3 isoforms with similar potency”
The paper relies on this without support.
The hydrophobic residues in the adenine-binding pocket are conserved across JNK isoforms.
“all of the hydrophobic residues are conserved in JNK isoforms.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In contrast, only three hydrophobic pockets (U A , U B , and U L ) are present in JNKs [Fig.2(A)].46,51,52”
From Molecular basis of MAP kinase regulation (2013) · cites this paper as [51]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Similarly, while both electrostatic pockets (W L, W U ) are present and occupied by different KIM peptides in ERK, p38, and FUS3, only the W L pocket is engaged by KIM peptides that bind specifically to JNKs [Fig.2(A)].”
From Molecular basis of MAP kinase regulation (2013) · cites this paper as [51]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“The two docking peptides adopted different main chain conformations between the contact points corresponding to the D-motif consensus sequence.”
From Specificity of Linear Motifs That Bind to a Common Mitogen-Activated Protein Kinase Docking Groove (2012) · cites this paper as [13]
Experimental — accuracy not yet measuredIn the citing paper
“The structure of JNK1 bound to a peptide from JIP1 protein showed that the peptide induced a rotation of the two lobes that distorted the active site, which was proposed as a mechanism for JIP1-mediated inhibition of JNK signaling (Heo et al., 2004).”
From Structural Mechanisms of Allostery and Autoinhibition in JNK Family Kinases (2012) · cites this paper as Heo et al., 2004
In the citing paper
“In the initial publication of JIP1-bound JNK (Heo et al., 2004), the interlobe rotation was apparent, but not the more substantial lobe opening, nor the mechanism of allosteric signal transduction, due to the inherent limitations of examining a single structure.”
From Structural Mechanisms of Allostery and Autoinhibition in JNK Family Kinases (2012) · cites this paper as Heo et al., 2004
In the citing paper
“At the structural level, MAPK docking is a well characterized protein-peptide interaction system (9, 12-16).”
From Specificity of Linear Motifs That Bind to a Common Mitogen-Activated Protein Kinase Docking Groove (2012) · cites this paper as [13]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Disorder of the phosphorylation loop
“missing residues 175-187 in JNK1-pepJIP1 and 212-216 in JNK3”
§ Structure determination and refinement
“The final model contained one JNK1 molecule of residues 9-172, 190-281, 287-336, and 349-363, one pepJIP1 molecule of residues 154-163, and 97 water molecules.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Interdomain rearrangement mediated by pepJIP1 binding
“pepMEF2A (saturated red) or pepMKK3b (saturated blue) bound in p38 MAPK (whitened blue)”
§ Interdomain rearrangement mediated by pepJIP1 binding
“The residues of pepJIP1, pepMEF2A, and pepMKK7 are labeled black, red, and blue, respectively.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Interdomain rearrangement mediated by pepJIP1 binding
“And the structure of E327 of JNK1 is compared with those of the corresponding glutamates of JNK3 (green), p38 (blue), and Erk2 (pink).”
§ pepJIP1 as a JNK-specific inhibitor
“And the fact that the structure of Glu329 of JNK1 complexed with pepJIP1 is actually identical to that of Glu367 of free JNK3”
Citations
Cites
Crystallography & NMR System: A New Software Suite for Macromolecular Structure Determination
Brünger, A. T., Adams, P. D., Clore, G. M., DeLano, W. L., Gros, P., Grosse‐Kunstleve, R. W., Jiang, J., Kuszewski, J. J., Nilges, M., Pannu, N., et al. (1998) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444998003254 · Cited by 15,723
Signal transduction by the JNK group of MAP kinases
Davis, R. J. (2000) · Cell · doi:10.1016/s0092-8674(00)00116-1 · Cited by 4,237
Mutation of the mouse klotho gene leads to a syndrome resembling ageing
Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., et al. (1997) · Nature · doi:10.1038/36285 · Cited by 3,837
A central role for JNK in obesity and insulin resistance
Hirosumi, J., Tuncman, G., Chang, L., Görgün, C. Z., Uysal, K. T., Maeda, K., Karin, M., & Hotamisligil, G. S. (2002) · Nature · doi:10.1038/nature01137 · Cited by 3,359
SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase
Bennett, B. L., Sasaki, D. T., Murray, B. W., O'Leary, E. C., Sakata, S. T., Xu, W., Leisten, J. C., Motiwala, A., Pierce, S., Satoh, Y., et al. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.251194298 · Cited by 2,558
Protein modules and signalling networks
Pawson, T. (1995) · Nature · doi:10.1038/373573a0 · Cited by 2,420
Signaling Through Scaffold, Anchoring, and Adaptor Proteins
Pawson, T., & Scott, J. D. (1997) · Science · doi:10.1126/science.278.5346.2075 · Cited by 2,256
The specificities of protein kinase inhibitors: an update
BAIN, J., McLAUCHLAN, H., ELLIOTT, M., & COHEN, P. (2003) · Biochemical Journal · doi:10.1042/bj20021535 · Cited by 1,369 · cited 4×
“The latest result demonstrates that the JNK specificity of SP600125 is not so excellent and this compound inhibits some protein kinases with similar or greater potency than JNK ( Bain et al, 2003 ).”
BackgroundResultInfluentialSelective interaction of JNK protein kinase isoforms with transcription factors.
Gupta, S., Barrett, T., Whitmarsh, A. J., Cavanagh, J., Sluss, H. K., Dérijard, B., & Davis, R. J. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00636.x · Cited by 1,341
Organization and regulation of mitogen-activated protein kinase signaling pathways
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Cited by
Sorted by citations
ERK1/2 MAP kinases: Structure, function, and regulation
Roskoski, R. J. (2012) · Pharmacological Research · doi:10.1016/j.phrs.2012.04.005 · Cited by 1,719
“Based upon X-ray crystallographic studies, the A-X- B sequences within D-sites bind to mouse p38 [110] and human JNK1 [111] in a hydrophobic groove flanked by helices D and E and the 7- 8 reverse turn.”
BackgroundThe JNK signal transduction pathway
Weston, C. R. (2002) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(01)00258-1 · Cited by 1,551
Mechanisms of specificity in protein phosphorylation
Ubersax, J. A., & Ferrell Jr, J. E. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2203 · Cited by 1,451
“Interestingly, other docking-site interactions appear to negatively regulate the docked kinas”
BackgroundDifferential regulation and properties of MAPKs
Raman, M., Chen, W., & Cobb, M. H. (2007) · Oncogene · doi:10.1038/sj.onc.1210392 · Cited by 1,430
“Structural insights and regulation via docking domains Crystal structures of JNK3a1 bound to adenylylimidodiphosphate (AMP-PNP) and JNK1 complexed with a peptide from the scaffold JNK interacting protein 1 (JIP1) showed overall architecture similar to ERK2 and p38 (Heo et al., 2004).”
BackgroundNolen, B. J., Taylor, S. S., & Ghosh, G. (2004) · Molecular Cell · doi:10.1016/j.molcel.2004.08.024 · Cited by 1,171
Metadata
- Authors
- Heo, Y., Kim, S., Seo, C. I., Kim, Y. K., Sung, B., Lee, H. S., Lee, J. I., Park, S., Kim, J. H., Hwang, K. Y., Hyun, Y., Jeon, Y. H., Ro, S., Cho, J. M., Lee, T. G., & Yang, C.
- Affiliations
- Seoul National University (KR)
- CrystalGenomics (South Korea) (KR)
- Yokohama City University (JP)
- Corresponding author
- Lee, Tae Gyu
- Yang, Chul‐Hak
- ORCID
- Venue
- The EMBO Journal
- Published
- 2004-05-13
- Volume
- 23
- Issue
- 11
- Pages
- 2185-2195
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC419904
- OpenAlex
- W2132108032
- Semantic Scholar
- ea6807d2e0dc42824be4ee4eab16e61e43294855
- Cited by
- 275
- References
- 46
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 6 · 2023: 6 · 2022: 6 · 2021: 5 · 2020: 9 · 2019: 7 · 2018: 7 · 2017: 9 · 2016: 10 · 2015: 10 · 2014: 14 · 2013: 17 · 2012: 21
- FWCI
- 7.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Korea Research Institute of Bioscience and Biotechnology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- JNK1, JIP1, SP600125, c-Jun N-terminal kinase, MAPK signaling, allosteric inhibition, kinase specificity, peptide binding, hinge motion, ternary complex structure, scaffold proteins, crystal structure
- MeSH terms
- Adenosine Triphosphate, Allosteric Regulation, Anthracenes, Arginine, Binding Sites, Calorimetry, HeLa Cells, Humans, Hydrogen Bonding, Leucine, Models, Molecular, Proline, Protein Binding, Protein Conformation, Transfection, Blotting, Western, Signal Transduction, Protein Structure, Tertiary, Crystallography, X-Ray, Glutamic Acid, Mitogen-Activated Protein Kinase 8, Adaptor Proteins, Signal Transducing
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-09-29, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-09-29 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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