The document discusses the Jun N-terminal kinase (JNK) signaling pathway which is involved in regulating cell proliferation, differentiation, and apoptosis. It describes the structure of JNK proteins and how they are activated through a kinase cascade involving MAP3Ks, MKK4/7, and ultimately JNK. JNK signaling can lead to either cell survival or apoptosis depending on stimuli and cell type. The document outlines how JNK mediates apoptosis through both nuclear and mitochondrial pathways, modulating pro-apoptotic and anti-apoptotic proteins to initiate caspase cascades. It concludes that JNK plays an essential role in both extrinsic and intrinsic apoptotic pathways by interacting with diverse proteins to efficiently execute the apoptotic program.

1. MAPK- JNK
Pathway
KRVS Chaitanya

2. Atomic structure
of JNK

3. • Ribbon diagram illustrates the three-dimensional
structure of the inactive (nonphosphorylated) form of
JNK3.
• The active site is occupied by the ATPanalog adenylyl
imidodiphosphate (yellow) and two Mg21 ions
(orange).
• The T-loop is colored red and the two sites of
activating phosphorylation (Thr and Tyr) are
indicated as red balls.
• Disordered regions are indicated with dashes.

4. •Jun N-terminal kinases (JNKs) belong to the
superfamily of MAP kinases that are involved in
the regulation of cell proliferation, differentiation
and apoptosis.
•Analyses of pathways regulated by JNKs have
shown that JNKs are indispensable for both cell
proliferation and apoptosis.

5. •Whether the activation of JNKs leads to cell
proliferation or apoptosis is dependent on the
stimuli and the cell type involved in such
activations .
•The JNK family of MAP kinases was initially
identified as ultraviolet (UV)-responsive protein
kinases involved in the transactivation of c-Jun
by phosphorylating the N-terminal Ser63 and
Ser73 residues.

6. •Although initial studies have shown that JNKs
can be activated by several different stimuli
including growth factors , cytokines and stress
factors.
•The observations that inflammatory cytokines
and many different cytotoxic as well as genotoxic
agents stimulate JNKs unraveled the critical role
of JNKs in mediating apoptotic signaling.

7. Signaling pathways that initiate apoptosis have
been broadly classified into::
•Extrinsic pathways initiated by death receptors such
as those of tumor necrosis factor (TNF)-a, TRAIL
and FAS-L, and
•Intrinsicpathways initiated by mitochondrial events.
JNK has been observed to have a central role in
both of these pathways.

8. •To date, multiple splice variants of JNKs encoded
by three distinct genes, namely JNK1, JNK2 and
JNK3, have been identified.
•JNKs form the last tier of the three-tier kinase
module consisting of MAP kinase kinase kinase
(MAP3K), MAP kinase kinase (MAP2K) and
MAP kinase (MAPK).

9. •In response to specific stimuli, the penultimate
dualspecificity kinase of the tier, either MKK4 or
MKK7, activates JNKs by phosphorylating the
Thr and Tyr residues of the TXY motif within the
activation loop of the respective JNKs.
•While MKK4 can activate both p38MAPK and
JNK, MKK7isspecifically involved in the
activation of JNKs.

10. •Both antiapoptotic and pro-apoptotic signals
converge on activating MKK4–JNK or MKK7–
JNK signaling nodes through specific MAP3Ks.
• JNKs in turn activate apoptotic signaling either
through the up regulation proapoptotic genes
through the transactivation of specific
transcription factors such as c-Jun or by directly
modulating the activities of mitochondrial pro-
and anti apoptoticproteins through
phosphorylation events.

11. •Although the apoptoticstimuli can also
involve the stimulation of p38MAPK, this
review specifically analyses our current
understanding of the mechanisms through
which JNK-signaling module is involved in
mediating apoptosis

12. Role of MAP3Ks in coupling stress stimuli
to JNK

13. Figure description::
• MAP3Ks and MAP2Ks involved in the activation of JNKs.
• At least 14 MAP3Ks have been shown to activate the MAP2Ks
MKK4 and/or MKK7.
• MKK4 can activate JNKs as well as p38MAPKs, whereas MKK7
specifically activates JNKs.
• MKK4 and MKK7 can activate all of the three isoforms of JNKs
by phosphorylating the Thr and Tyr residues of the TXY motif.
• JNK, Jun N-terminal kinase; MAP2K, MAP kinase kinase;
MAP3K, MAP kinase kinase kinase.

14. The JNK-Dependent Apoptotic Signaling
Pathway

15. Figure description::
• The caspase apoptotic machinery is illustrated in a simplified
cartoon.
• Effector caspases, including caspase-3, are activated by
initiator caspases that are activated by cell surface death
receptors (caspase-8) and by the mitochondrial pathway
(caspase-9).
• JNK is not required for death receptor signaling, but is
required for caspase-9 activation by the mitochondrial
pathway.
• Potential targets of JNK include members of the Bcl2 group
of apoptotic regulatory proteins

16. Nucleus-and mitochondria-targeted signaling by JNK

17. Figure Description::
•JNK can promote apoptosis by two distinct
mechanisms.
•In the first mechanism targeted at the nuclear events,
activated JNK translocates to the nucleus and
transactivates c-Jun and other target transcription
factors (TF).
•JNK can promote apoptosis by increasing the
expression of pro-apoptotic genes through the
transactivation of c-Jun/AP1-dependent or p53/73
protein-dependent mechanisms .

18. Contd….
• In pathways directed at mitochondrial apoptotic proteins,
activated JNK translocates to mitochondria.
• There, JNK can phosphorylate the BH3-only family of Bcl2
proteins to antagonize the antiapoptotic activity of Bcl2 or
Bcl-XL.
• In addition, JNK can stimulate the release of cytochrome c
(Cyt C) from the mitochondrial inner membrane through a
Bid-Bax-dependent mechanism, promoting the formation of
apoptosomes consisting of cytochrome c, caspase-9 (Casp 9)
and Apaf-1.

19. Contd….
• This complex initiates the activation of caspase-9-dependent
caspase cascade.
• In another mechanism, JNK can promote the release of
Smac/Diablo (Smac) that can inhibit the TRAF2/IAP1
inhibitory complex, thereby relieving the inhibition on
caspase-8 to initiate caspase activation.
• In addition, by phosphorylating BAD and its sequestering
partner 14-3-3, JNK can promote BAD-mediated
neutralization of the Bcl2 family of antiapoptotic proteins.

20. Contd….
• Finally, JNK can phosphorylate Bcl2 for suppressing
its antiapoptotic activity.
• These nuclear and mitochondrial events regulated by
JNK need not be mutually exclusive. JNK, Jun N-
terminal kinase; TRAF2, TNF-receptor-associated
factor 2.

21. Role of JNK Pathway
• JNKs in apoptotic signaling
• Nuclear signaling of JNK in the regulation of
apoptosis
• Mitochondrial signaling of JNK in the regulation of
apoptosis
• JNK in Signaling Cell Survival

23. Discussion
• An overview of apoptotic pathways indicates that JNK
signaling is involved in the extrinsic apoptotic
pathway initiated by death receptors as well as the
intrinsic pathway initiated at the mitochondria.
• In response to both the extrinsic and intrinsic
apoptotic stimuli, JNK plays an essential role through
its ability to interact and modulate the activities of
diverse pro-and antiapoptotic proteins.

24. • Through the coordinated regulation of the nuclear and
mitochondrial events, JNK ensures the efficient
execution of apoptosis.
• With the identification of primary apoptotic signaling
nodes regulated by JNK, the finer details of JNK
signaling in apoptosis, specifically in relation to other
growth-stimulating stimuli, are finally emerging and
this should unravel novel therapeutic targets for
diverse pathological conditions such as Alzheimer’s
disease and cancer.

25. Thank You