SEMINAR (M.Sc II Sem) by Deepak chawhan.pdf

CONTENT
❖ Introduction
❖ Structure of JAKS-STAKS Pathway
❖ Mechanism of JAK-STAK Signaling Pathway
❖ Regulation of the JAK-STAK Pathway
❖ Clinical Significances
❖ References

INTRODUCTION
JAK stands for Janus Kinase and STAT stands for Signal Transducer and Activator of
Transcription Proteins. The JAK-STAT signaling pathway is a chain of interactions
between proteins in a cell, and is involved in processes such as immunity, cell division,
cell death and tumour formation. The pathway communicates information from chemical
signals outside of a cell to the cell nucleus, resulting in the activation of genes through a
process called transcription. There are three key parts of JAK-STAT signalling: Janus
kinases (JAKs), signal transducer and activator of transcription proteins (STATs), and
receptors (which bind the chemical signals). Disrupted JAK-STAT signalling may lead to
a variety of diseases, such as skin conditions, cancers, and disorders affecting the
immune system.

STRUCTURE OF JAKs-STAKs PATHWAY
There are four JAK proteins: JAK1, JAK2, JAK3 and TYK2. JAKs contains a FERM
domain (approximately 400 residues), an SH2-related domain (approximately 100
residues), a kinase domain (approximately 250 residues) and a pseudokinase domain
(approximately 300 residues). The kinase domain is vital for JAK activity, since it allows
JAKs to phosphorylate (add phosphate groups to) proteins.
There are seven STAT proteins: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and
STAT6. STAT proteins contain many different domains, each with a different function, of
which the most conserved region is the SH2 domain.The SH2 domain is formed of 2
α-helices and a β-sheet and is formed approximately from residues 575–680.STATs also
have transcriptional activation domains (TAD), which are less conserved and are
located at the C-terminus.[4] In addition, STATs also contain: tyrosine activation,
amino-terminal, linker, coiled-coil and DNA-binding domains.

MECHANISM OF JAK-STAK PATHWAYS
Figure - Key steps of the JAK-STAT pathway. JAK-STAT signalling is made of three major
proteins: cell-surface receptors, Janus kinases (JAKs), and signal transducer and activator of
transcription proteins (STATs). Once a ligand (red triangle) binds to the receptor, JAKs add
phosphates (red circles) to the receptor. Two STAT proteins then bind to the phosphates, and
then the STATs are phosphorylated by JAKs to form a dimer. The dimer enters the nucleus,
binds to DNA, and causes transcription of target genes. The JAK-STAT system consists of three
main components: (1) a receptor (green), which penetrates the cell membrane, (2) Janus kinase
(JAK) (yellow), which is bound to the receptor, and (3) Signal Transducer and Activator of
Transcription (STAT) (blue), which carries the signal into the nucleus and DNA.
The red dots are phosphates. After the cytokine binds to the receptor, JAK adds a phosphate to
(phosphorylates) the receptor. This attracts the STAT proteins, which are also phosphorylated
and bind to each other, forming a pair (dimer). The dimer moves into the nucleus, binds to the
DNA, and causes transcription of genes. Enzymes that add phosphate groups are called protein
kinases.
The binding of various ligands, usually cytokines, such as interferons and
interleukins, to cell-surface receptors, causes the receptors to dimerize, which brings
the receptor-associated JAKs into close proximity.The JAKs then phosphorylate each
other on tyrosine residues located in regions called activation loops, through a process
called transphosphorylation, which increases the activity of their kinase domains. The
activated JAKs then phosphorylate tyrosine residues on the receptor, creating binding
sites for proteins possessing SH2 domains. STATs then bind to the phosphorylated
tyrosines on the receptor using their SH2 domains, and then they are
tyrosine-phosphorylated by JAKs, causing the STATs to dissociate from the receptor. At
least STAT5 requires glycosylation at threonine 92 for strong STAT5 tyrosine
phosphorylation.These activated STATs form hetero- or homodimers, where the SH2

domain of each STAT binds the phosphorylated tyrosine of the opposite STAT, and the
dimer then translocates to the cell nucleus to induce transcription of target genes.
STATs may also be tyrosine-phosphorylated directly by receptor tyrosine kinases - but
since most receptors lack built-in kinase activity, JAKs are usually required for
signalling.
Movement of STATs from the cytosol to the nucleus -
To move from the cytosol to the nucleus, STAT dimers have to pass through nuclear
pore complexes (NPCs), which are protein complexes present along the nuclear
envelope that control the flow of substances in and out of the nucleus. To enable STATs
to move into the nucleus, an amino acid sequence on STATs, called the nuclear
localization signal (NLS), is bound by proteins called importins.Once the STAT dimer
(bound to importins) enters the nucleus, a protein called Ran (associated with GTP)
binds to the importins, releasing them from the STAT dimer.The STAT dimer is then free
in the nucleus.
Specific STATs appear to bind to specific importin proteins. For example, STAT3
proteins can enter the nucleus by binding to importin α3 and importin α6. On the other
hand, STAT1 and STAT2 bind to importin α5. Studies indicate that STAT2 requires a
protein called interferon regulatory factor 9 (IRF9) to enter the nucleus.Not as much is
known about nuclear entrance of other STATs, but it has been suggested that a
sequence of amino acids in the DNA-binding domain of STAT4 might allow nuclear
import; also, STAT5 and STAT6 can both bind to importin α3. In addition, STAT3, STAT5
and STAT6 can enter the nucleus even if they are not phosphorylated at tyrosine
residues.
Role of post-translational modifications -
After STATs are made by protein biosynthesis, they have non-protein molecules
attached to them, called post-translational modifications. One example of this is tyrosine
phosphorylation (which is fundamental for JAK-STAT signalling), but STATs experience
other modifications, which may affect STAT behaviour in JAK-STAT signalling. These
modifications include: methylation, acetylation and serine phosphorylation.
● Methylation - STAT3 can be dimethylated (have two methyl groups) on a lysine
residue, at position 140, and it is suggested that this could reduce STAT3 activity.
There is debate as to whether STAT1 is methylated on an arginine residue (at
position 31), and what the function of this methylation could be.

● Acetylation. STAT1, STAT2, STAT3, STAT5 and STAT6 have been shown to be
acetylated. STAT1 may have an acetyl group attached to lysines at positions 410
and 413, and as a result, STAT1 can promote the transcription of apoptotic genes
- triggering cell death. STAT2 acetylation is important for interactions with other
STATs, and for the transcription of anti-viral genes.
Acetylation of STAT3 has been suggested to be important for its dimerization,
DNA-binding and gene-transcribing ability, and IL-6 JAK-STAT pathways that use
STAT3 require acetylation for transcription of IL-6 response genes. STAT5 acetylation
on lysines at positions 694 and 701 is important for effective STAT dimerization in
prolactin signalling. Adding acetyl groups to STAT6 is suggested to be essential for
gene transcription in some forms of IL-4 signalling, but not all the amino acids which are
acetylated on STAT6 are known.
● Serine phosphorylation. Most of the seven STATs (except STAT2) undergo serine
phosphorylation. Serine phosphorylation of STATs has been shown to reduce
gene transcription. It is also required for the transcription of some target genes of
the cytokines IL-6 and IFN- γ. It has been proposed that phosphorylation of
serine can regulate STAT1 dimerization, and that continuous serine
phosphorylation on STAT3 influences cell division.
Recruitment of co-activators -
Like many other transcription factors, STATs are capable of recruiting co-activators such
as CBP and p300, and these co-activators increase the rate of transcription of target
genes. The coactivators are able to do this by making genes on DNA more accessible
to STATs and by recruiting proteins needed for transcription of genes. The interaction
between STATs and coactivators occurs through the transactivation domains (TADs) of
STATs. The TADs on STATs can also interact with histone acetyltransferases (HATs);
these HATs add acetyl groups to lysine residues on proteins associated with DNA called
histones. Adding acetyl groups removes the positive charge on lysine residues, and as
a result there are weaker interactions between histones and DNA, making DNA more
accessible to STATs and enabling an increase in the transcription of target genes.

Integration with other signaling pathways -
Figure - An example of the integration between JAK-STAT, MAPK/ERK and PI3K/AKT/mTOR
signalling pathways. JAKs phosphorylate cytokine receptors which can bind a protein called
Grb2. Grb2 then activates SOS proteins which stimulate MAPK signalling. MAPK can also
phosphorylate STATs. Phosphorylated cytokine receptors can also be bound by PI3K, which
allows activation of AKT. ERK, STATs and Akt can then interact with other proteins. The receptor
is not shown as a dimer, and only one side of the receptors are shown phosphorylated for
simplification.
JAK-STAT signalling is able to interconnect with other cell-signalling
pathways, such as the PI3K/AKT/mTOR pathway. When JAKs are activated and
phosphorylate tyrosine residues on receptors, proteins with SH2 domains (such as
STATs) are able bind to the phosphotyrosines, and the proteins can carry out their
function. Like STATs, the PI3K protein also has an SH2 domain, and therefore it is also
able to bind to these phosphorylated receptors. As a result, activating the JAK-STAT
pathway can also activate PI3K/AKT/mTOR signalling.
JAK-STAT signalling can also integrate with the MAPK/ERK pathway.
Firstly, a protein important for MAPK/ERK signalling, called Grb2, has an SH2 domain,
and therefore it can bind to receptors phosphorylated by JAKs (in a similar way to
PI3K). Grb2 then functions to allow the MAPK/ERK pathway to progress. Secondly, a
protein activated by the MAPK/ERK pathway, called MAPK (mitogen-activated protein
kinase), can phosphorylate STATs, which can increase gene transcription by STATs.
However, although MAPK can increase transcription induced by STATs, one study
indicates that phosphorylation of STAT3 by MAPK can reduce STAT3 activity.
One example of JAK-STAT signalling integrating with other pathways is Interleukin-2
(IL-2) receptor signaling in T cells. IL-2 receptors have γ (gamma) chains, which are
associated with JAK3, which then phosphorylates key tyrosines on the tail of the

receptor. Phosphorylation then recruits an adaptor protein called Shc, which activates
the MAPK/ERK pathway, and this facilitates gene regulation by STAT5.
Alternative signalling pathway -
An alternative mechanism for JAK-STAT signalling has also been suggested. In this
model, SH2 domain-containing kinases, can bind to phosphorylated tyrosines on
receptors and directly phosphorylate STATs, resulting in STAT dimerization. Therefore,
unlike the traditional mechanism, STATs can be phosphorylated not just by JAKs, but by
other receptor-bound kinases. So, if one of the kinases (either JAK or the alternative
SH2-containing kinase) cannot function, signalling may still occur through activity of the
other kinase.This has been shown experimentally.
Role in cytokine receptor signalling -
Given that many JAKs are associated with cytokine receptors, the JAK-STAT signalling
pathway plays a major role in cytokine receptor signalling. Since cytokines are
substances produced by immune cells that can alter the activity of neighbouring cells,
the effects of JAK-STAT signalling are often more highly seen in cells of the immune
system. For example, JAK3 activation in response to IL-2 is vital for lymphocyte
development and function. Also, one study indicates that JAK1 is needed to carry out
signalling for receptors of the cytokines IFNγ, IL-2, IL-4 and IL-10.
The JAK-STAT pathway in cytokine receptor signalling can activate STATs, which can
bind to DNA and allow the transcription of genes involved in immune cell division,
survival, activation and recruitment. For example, STAT1 can enable the transcription of
genes which inhibit cell division and stimulate inflammation. Also, STAT4 is able to
activate NK cells (natural killer cells), and STAT5 can drive the formation of white blood
cells. In response to cytokines, such as IL-4, JAK-STAT signalling is also able to
stimulate STAT6, which can promote B-cell proliferation, immune cell survival, and the
production of an antibody called IgE.
Role in development -
JAK-STAT signalling plays an important role in animal development. The pathway can
promote blood cell division, as well as differentiation (the process of a cell becoming
more specialised). In some flies with faulty JAK genes, too much blood cell division can
occur, potentially resulting in leukaemia. JAK-STAT signalling has also been associated
with excessive white blood cell division in humans and mice.

The signalling pathway is also crucial for eye development in the fruit fly (Drosophila
melanogaster). When mutations occur in genes coding for JAKs, some cells in the eye
may be unable to divide, and other cells, such as photoreceptor cells, have been shown
not to develop correctly.
The entire removal of a JAK and a STAT in Drosophila causes death of Drosophila
embryos, whilst mutations in the genes coding for JAKs and STATs can cause
deformities in the body patterns of flies, particularly defects in forming body segments.
One theory as to how interfering with JAK-STAT signalling might cause these defects is
that STATs may directly bind to DNA and promote the transcription of genes involved in
forming body segments, and therefore by mutating JAKs or STATs, flies experience
segmentation defects. STAT binding sites have been identified on one of these genes,
called even-skipped (eve), to support this theory. Of all the segment stripes affected by
JAK or STAT mutations, the fifth stripe is affected the most, the exact molecular reasons
behind this are still unknown.

REGULATION OF JAK-STAK PATHWAYS
Given the importance of the JAK-STAT signalling pathway, particularly in cytokine
signalling, there are a variety of mechanisms that cells possess to regulate the amount
of signalling that occurs. Three major groups of proteins that cells use to regulate this
signalling pathway are protein inhibitors of activated STAT (PIAS), protein tyrosine
phosphatases (PTPs) and suppressors of cytokine signalling (SOCS).
Protein inhibitors of activated STATs (PIAS) -
Figure - Three ways PIAS proteins can inhibit JAK-STAT signaling. (A) Adding a SUMO group
to STATs can block their phosphorylation, which prevents STATs entering the nucleus. (B) HDAC
(histone deacetylase) recruitment can remove acetyl modifications on histones, lowering gene
expression. (C) PIAS can also prevent STATs binding to DNA
PIAS are a four-member protein family made of: PIAS1, PIAS3, PIASx,
and PIASγ. The proteins add a marker, called SUMO (small ubiquitin-like modifier), onto
other proteins – such as JAKs and STATs, modifying their function. The addition of a
SUMO group onto STAT1 by PIAS1 has been shown to prevent activation of genes by
STAT1. Other studies have demonstrated that adding a SUMO group to STATs may
block phosphorylation of tyrosines on STATs, preventing their dimerization and inhibiting
JAK-STAT signalling. PIASγ has also been shown to prevent STAT1 from functioning.
PIAS proteins may also function by preventing STATs from binding to DNA (and
therefore preventing gene activation), and by recruiting proteins called histone
deacetylases (HDACs), which lower the level of gene expression.

Protein tyrosine phosphatases (PTPs) -
Since adding phosphate groups on tyrosines is such an important part of how the
JAK-STAT signalling pathway functions, removing these phosphate groups can inhibit
signalling. PTPs are tyrosine phosphatases, so are able to remove these phosphates
and prevent signalling. Three major PTPs are SHP-1, SHP-2 and CD45.
● SHP-1- SHP-1 is mainly expressed in blood cells. It contains two SH2 domains
and a catalytic domain (the region of a protein that carries out the main function
of the protein) - the catalytic domain contains the amino acid sequence
VHCSAGIGRTG (a sequence typical of PTPs). As with all PTPs, a number of
amino acid structures are essential for their function: conserved cysteine,
arginine and glutamine amino acids, and a loop made of tryptophan, proline and
aspartate amino acids (WPD loop). When SHP-1 is inactive, the SH2 domains
interact with the catalytic domain, and so the phosphatase is unable to function.
When SHP-1 is activated however, the SH2 domains move away from the
catalytic domain, exposing the catalytic site and therefore allowing phosphatase
activity. SHP-1 is then able to bind and remove phosphate groups from the JAKs
associated with receptors, preventing the transphosphorylation needed for the
signalling pathway to progress.
One example of this is seen in the JAK-STAT signalling pathway mediated by the
erythropoietin receptor (EpoR). Here, SHP-1 binds directly to a tyrosine residue
(at position 429) on EpoR and removes phosphate groups from the
receptor-associated JAK2. The ability of SHP-1 to negatively regulate the
JAK-STAT pathway has also been seen in experiments using mice lacking
SHP-1. These mice experience characteristics of autoimmune diseases and
show high levels of cell proliferation, which are typical characteristics of an
abnormally high level of JAK-STAT signalling. Additionally, adding methyl groups
to the SHP-1 gene (which reduces the amount of SHP-1 produced) has been
linked to lymphoma (a type of blood cancer).
However, SHP-1 may also promote JAK-STAT signalling. A study in 1997 found
that SHP-1 potentially allows higher amounts of STAT activation, as opposed to
reducing STAT activity. A detailed molecular understanding for how SHP-1 can
both activate and inhibit the signalling pathway is still unknown.
● SHP-2 - SHP-2 has a very similar structure to SHP-1, but unlike SHP-1, SHP-2 is
produced in many different cell types - not just blood cells. Humans have two

SHP-2 proteins, each made up of 593 and 597 amino acids. The SH2 domains of
SHP-2 appear to play an important role in controlling the activity of SHP-2. One
of the SH2 domains binds to the catalytic domain of SHP-2, to prevent SHP-2
functioning. Then, when a protein with a phosphorylated tyrosine binds, the SH2
domain changes orientation and SHP-2 is activated. SHP-2 is then able to
remove phosphate groups from JAKs, STATs and the receptors themselves - so,
like SHP-1, can prevent the phosphorylation needed for the pathway to continue,
and therefore inhibit JAK-STAT signalling. Like SHP-1, SHP-2 is able to remove
these phosphate groups through the action of the conserved cysteine, arginine,
glutamine and WPD loop.
Negative regulation by SHP-2 has been reported in a number of experiments -
one example has been when exploring JAK1/STAT1 signalling, where SHP-2 is
able to remove phosphate groups from proteins in the pathway, such as STAT1.
In a similar manner, SHP-2 has also been shown to reduce signalling involving
STAT3 and STAT5 proteins, by removing phosphate groups.
Like SHP-1, SHP-2 is also believed to promote JAK-STAT signalling in some
instances, as well as inhibit signalling. For example, one study indicates that
SHP-2 may promote STAT5 activity instead of reducing it. Also, other studies
propose that SHP-2 may increase JAK2 activity, and promote JAK2/STAT5
signalling. It is still unknown how SHP2 can both inhibit and promote JAK-STAT
signalling in the JAK2/STAT5 pathway; one theory is that SHP-2 may promote
activation of JAK2, but inhibit STAT5 by removing phosphate groups from it.
● CD45 - CD45 is mainly produced in blood cells. In humans it has been shown to
be able to act on JAK1 and JAK3, whereas in mice, CD45 is capable of acting on
all JAKs. One study indicates that CD45 can reduce the amount of time that
JAK-STAT signalling is active. The exact details of how CD45 functions is still
unknown.
Suppressors of cytokine signalling (SOCS) -
There are eight protein members of the SOCS family: cytokine-inducible SH2
domain-containing protein (CISH), SOCS1, SOCS2, SOCS3, SOCS4, SOCS5, SOCS6,
and SOCS7, each protein has an SH2 domain and a 40-amino-acid region called the
SOCS box. The SOCS box can interact with a number of proteins to form a protein
complex, and this complex can then cause the breakdown of JAKs and the receptors
themselves, therefore inhibiting JAK-STAT signalling. The protein complex does this by
allowing a marker called ubiquitin to be added to proteins, in a process called

ubiquitination, which signals for a protein to be broken down. The proteins, such as
JAKs and the receptors, are then transported to a compartment in the cell called the
proteasome, which carries out protein breakdown.
SOCS can also function by binding to proteins involved in JAK-STAT signalling and
blocking their activity. For example, the SH2 domain of SOCS1 binds to a tyrosine in the
activation loop of JAKs, which prevents JAKs from phosphorylating each other. The
SH2 domains of SOCS2, SOCS3 and CIS bind directly to receptors themselves. Also,
SOCS1 and SOCS3 can prevent JAK-STAT signalling by binding to JAKs, using
segments called kinase inhibitory regions (KIRs) and stopping JAKs binding to other
proteins. The exact details of how other SOCS function is less understood.
Regulator Positive or Negative
regulation
Function
PTPs
SHP-1 and SHP-2:
Negative, but could
also be positive.
CD45, PTP1B,
TC-PTP: Negative
Removes phosphate
groups from receptors,
JAKs and STATs
SOCS Negative
SOCS1 and SOCS3
block JAKs active sites
using KIR domains.
SOCS2, SOCS3 and
CIS can bind
receptors. SOCS1 and
SOCS3 can signal
JAKs and receptor for
degradation.
PIAS Negative Add SUMO group to
STATs to inhibit STAT
activity. Recruit
histone deacetylases
to lower gene
expression. Prevent
STATs binding to DNA.

CLINICAL SIGNIFICANCE
Since the JAK-STAT pathway plays a major role in many fundamental processes, such
as apoptosis and inflammation, dysfunctional proteins in the pathway may lead to a
number of diseases. For example, alterations in JAK-STAT signalling can result in
cancer and diseases affecting the immune system, such as severe combined
immunodeficiency disorder (SCID).
Immune system-related diseases -
JAK3 can be used for the signalling of IL-2, IL-4, IL-15 and IL-21 (as well as other
cytokines); therefore patients with mutations in the JAK3 gene often experience issues
affecting many aspects of the immune system. For example, non-functional JAK3
causes SCID, which results in patients having no NK cells, B cells or T cells, and this
would make SCID individuals susceptible to infection. Mutations of the STAT5 protein,
which can signal with JAK3, has been shown to result in autoimmune disorders.
It has been suggested that patients with mutations in STAT1 and STAT2 are often more
likely to develop infections from bacteria and viruses. Also, STAT4 mutations have been
associated with rheumatoid arthritis, and STAT6 mutations are linked to asthma.
Patients with a faulty JAK-STAT signalling pathway may also experience skin disorders.
For example, non-functional cytokine receptors, and overexpression of STAT3 have
both been associated with psoriasis (an autoimmune disease associated with red, flaky
skin). STAT3 plays an important role in psoriasis, as STAT3 can control the production
of IL-23 receptors, and IL-23 can help the development of Th17 cells, and Th17 cells
can induce psoriasis. Also, since many cytokines function through the STAT3
transcription factor, STAT3 plays a significant role in maintaining skin immunity. In
addition, because patients with JAK3 gene mutations have no functional T cells, B cells
or NK cells, they would more likely to develop skin infections.
Cancer -
Cancer involves abnormal and uncontrollable cell growth in a part of the body.
Therefore, since JAK-STAT signalling can allow the transcription of genes involved in
cell division, one potential effect of excessive JAK-STAT signalling is cancer formation.
High levels of STAT activation have been associated with cancer; in particular, high
amounts of STAT3 and STAT5 activation is mostly linked to more dangerous tumours.
For example, too much STAT3 activity has been associated with increasing the
likelihood of melanoma (skin cancer) returning after treatment and abnormally high

levels of STAT5 activity have been linked to a greater probability of patient death from
prostate cancer. Altered JAK-STAT signalling can also be involved in developing breast
cancer. JAK-STAT signalling in mammary glands (located within breasts) can promote
cell division and reduce cell apoptosis during pregnancy and puberty, and therefore if
excessively activated, cancer can form. High STAT3 activity plays a major role in this
process, as it can allow the transcription of genes such as BCL2 and c-Myc, which are
involved in cell division.
Mutations in JAK2 can lead to leukaemia and lymphoma..Specifically, mutations in
exons 12, 13, 14 and 15 of the JAK2 gene are proposed to be a risk factor in developing
lymphoma or leukemia. Additionally, mutated STAT3 and STAT5 can increase
JAK-STAT signalling in NK and T cells, which promotes very high proliferation of these
cells, and increases the likelihood of developing leukaemia. Also, a JAK-STAT signalling
pathway mediated by erythropoietin (EPO), which usually allows the development of red
blood cells, may be altered in patients with leukemia.
Treatments -
Since excessive JAK-STAT signalling is responsible for some cancers and immune
disorders, JAK inhibitors have been proposed as drugs for therapy. For instance, to
treat some forms of leukaemia, targeting and inhibiting JAKs could eliminate the effects
of EPO signalling and perhaps prevent the development of leukaemia. One example of
a JAK inhibitor drug is Ruxolitinib, which is used as a JAK2 inhibitor. STAT inhibitors are
also being developed, and many of the inhibitors target STAT3. It has been reported that
therapies which target STAT3 can improve the survival of patients with cancer. Another
drug, called Tofacitinib, has been used for psoriasis and rheumatoid arthritis treatment,
and has been recently approved for Crohn's Disease and Ulcerative Colitis treatment.

REFERENCES
● David L. Nelson, Michael M. Cox, Lehninger - Principles of
Biochemistry, Sixth Edition, w.h.freeman, P.P- 457- 458
● Victor W. Rodwell, David A. Bender, Kathleen M. Botham, Peter J.
Kennelly, P. Anthony Weil, Harper's - Illustrated Biochemistry,
Twenty Sixth Edition, Lange, P.P. - 467

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