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JAK/STAT Pathway

Chapter January 2012


DOI: 10.1007/978-3-540-29807-6_242

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Marissa K Caldow (Trenerry) David Cameron-Smith


University of Melbourne University of Auckland
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J
and JAK2. JAK dimers reside with the receptor subunit
JAK and undergo tyrosine auto-phosphorylation upon cyto-
kine binding. Phosphorylation of JAK receptors creates
Janus kinase.
docking sites for STAT-binding domains, thereby
recruiting STATs to the JAK-receptor complex. JAKS
then phosphorylate specic tyrosine residues located in
JAK/STAT Pathway the STAT C-terminal SH2 domain to facilitate STAT
dimerization and translocation. Seven STAT family mem-
MARISSA K. CALDOW1, DAVID CAMERON-SMITH2 bers have been characterized: STAT1, STAT2, STAT3,
1
Molecular Nutrition Unit, School of Exercise and STAT4, STAT5a, STAT5b, and STAT6. Tyrosine phosphor-
Nutrition Sciences, Deakin University, Burwood, VIC, ylation sites of STATs interact to form homo- or
Australia heterodimers, which translocate from the cytoplasm to
2
University of Auckland, Auckland, New Zealand the nucleus to initiate gene transcription. Additionally,
several STATs undergo serine phosphorylation; however it
is relatively unknown what role this serves in STAT activa-
Synonyms tion, and it may differ between the family members [1].
Janus kinases (JAK); Signal transducers and activators of The JAK/STAT pathway is tightly regulated by a neg-
transcription (STAT) ative feedback mechanism coordinated by suppressors of
cytokine signaling known as SOCS. The general mech-
Definition anistic role for the SOCS proteins is to regulate the strength
JAK/ STAT signaling is activated by a wide array of and duration of STAT-dependent cytokine-induced signal-
cytokines and growth factors leading to the stimulation ing. The SOCS family consists of eight members, SOCS1 to
of cell proliferation, differentiation, and apoptosis. SOCS7 and CIS (cytokine-inducible SH2-containing pro-
Upon binding of these ligands to gp130, subsequent tein), which are present at low abundance in unstimulated
dimerization of JAKs induces STATs phosphorylation cells, yet are rapidly upregulated in response to a range of
and nuclear translocation, where STATs interact with cytokines and growth factors. SOCS proteins also contain a
DNA-binding sequences to initiate gene transcription. SH2 domain in addition to a SOCS box, which is thought to
This signaling cascade is utilized by countless cell types. be involved in the proteasomal degradation of JAKs. SOCS
Surprisingly, there is little documented about this pathway proteins can deactivate JAK/STAT signaling via different
in human skeletal muscle, an important tissue for both mechanisms; inhibition of JAKS by directly binding to the
physical function and metabolic health. receptor; competition with other SH2-domain-signaling
molecules for binding sites on the receptor; targeting of
Basic Mechanisms the receptor complex for proteasomal ubiquitination; and
degradation through the SOCS box. SOCS proteins are
Molecular Description critical for the regulation of a plethora of cytokines and
JAKs are non-receptor tyrosine kinases. In mammals, the growth factors. As a result, SOCS deciency can lead to
JAK family consists of four members: JAK1, JAK2, JAK3, a range of developmental defects; however it is possible that
and TYK2. JAK1, JAK2, and TYK2 are ubiquitously other SOCS members can correct for the loss of specic
expressed while JAK3 is predominantly found in cells of SOCS proteins [2] (Fig. 1).
the hematopoietic system. JAKs are found in the cytosol
and associate with a variety of cytokine and growth factor Skeletal Muscle and JAK/STAT
receptors; therefore a large number of cytokines and Understanding the fundamental mechanisms underlying
growth factors are functionally dependent on JAK1 muscle growth has the potential to provide new therapies

Frank C. Mooren (ed.), Encyclopedia of Exercise Medicine in Health and Disease, DOI 10.1007/978-3-540-29807-6,
# Springer-Verlag Berlin Heidelberg 2012
496 J JAK/STAT Pathway

P JAK JAK
P

gp130
SOCS3

P
STAT STAT
P

P
STAT
P STAT

P
STAT TIMP1
VEGF

P
STAT MnSOD c-MYC
angiogenesis
cyclins JUNB
bcl-XL
iNOS
c-FOS
survival hypertrophy

JAK/STAT Pathway. Fig. 1 The JAK/STAT transcription pathway. When growth factors and cytokines bind to the gp130 receptor,
JAKs are phosphorylated. This phosphorylation leads to STATs phosphorylation and subsequent dimerization of this molecule.
The phosphorylated STAT dimer translocates to the nucleus where it activates the transcription of genes associated with cell
proliferation and survival

to treat muscle disease, improve recovery, and combat myogenesis have been delineated. LIF-mediated satellite
age-related muscle loss. Importantly, the molecules cell proliferation occurs via JAK1/STAT1/STAT3 whereby
and signaling pathways that regulate muscle regeneration STAT1 must cooperate with STAT3 to induce proliferation
might be manipulated or mimicked to augment and prevent premature differentiation. For differentiation,
the growth of skeletal muscle. Inammation has emerged myogenic gene expression is regulated by LIF-induced
as an essential adaptive response needed for muscular JAK2/STAT2/STAT3 activation. Consistent with in vitro
adaptation and repair. Inammatory mediators that are functioning, IL-6, LIF, and STAT3 are localized in
released during this period, such as interleukin-6 (IL-6)- regenerating muscle indicating a role for STAT3 during
like cytokines, are utilized by the many signaling pathways the proliferative phase of muscle regeneration. Importantly,
which participate in adaptation and repair, importantly, in rat skeletal muscle in vivo, STAT3 is undetectable in
JAK/STAT. uninjured muscles, yet following muscle crush injury
STAT3 is phosphorylated in regenerating muscle [3, 4].
Myogenesis
STAT3 is an integral component of the proliferation/differ- Hypertrophy
entiation process in skeletal muscle. The IL-6/STAT3 and Hypertrophy, the rebuilding and remodeling of muscle, is
LIF/STAT3 pathways facilitate satellite cell proliferation, initiated after damage is inicted on the muscle. This
differentiation, and hypertrophy of skeletal muscle process occurs in both skeletal and cardiac muscles.
cells. Specic pathways involving LIF signaling in Cardiac hypertrophy is a protective mechanism induced
Janus Kinases (JAK) J 497

by increased stress on the heart; it is initiated to allow factor-a (TNF-a) which have been suggested to play
the heart to maintain its regular cardiac output. major roles in the functional decline of older individuals.
In a hypertrophied heart, cardiac muscle undergoes struc- The expression levels of STAT isoforms are thought to
tural changes at the cellular level coordinated by cytokines decrease with age in different cell types, particularly
and growth factors acting through various signaling in the brain and cardiac tissue. However, this may relate
cascades. This process results in wall thickness increasing to the abundance of circulating JAK/STAT activators.
to lower the stress placed on ventricle walls. gp130, IL-6 and In skeletal muscle, this signaling cascade may become
IL-6R are essential for cardiac hypertrophy, as well as LIF, dysfunctional as we age in response to cellular stress.
STAT3, and SOCS3 [1]. Similarly, skeletal muscle STAT3 signaling following acute resistance exercise is still
undergoes bouts of muscle growth in response to the stress heightened in the skeletal muscle of older individuals
placed on the muscle during resistance exercise, which is which occurs together with induction of SOCS3; however
mediated via equivalent signaling events. However, in there appears to be an inefciency of SOCS3 mRNA trans-
skeletal muscle there is limited information for the role lation with age. Although the signicance of this altered
of JAK/STAT in hypertrophy. Nevertheless, IL-6 and LIF signaling in skeletal muscle remains to be determined, the
are important mediators of skeletal muscle hypertrophy impaired regulation of cytokine signaling associated with
in response to increased muscle loading evident with delayed SOCS3 transcription may contribute to the
resistance exercise. IL-6 is also important for satellite diminished regenerative capacity and decline in skeletal
cell incorporation into the already existing myober for muscle function seen with age [5].
skeletal muscle regeneration [5]. There has been considerable progress in under- J
standing the mechanisms of JAK/STAT signaling since
Exercise it was rst described. While it is clear that this tran-
Growth factors and cytokines are central mediators scription pathway is critical for the regulation of many
of repair and adaptation in skeletal muscle. Although biological and pathological processes, a gap remains
the exact signaling pathways involved have yet to be fully how this pathway may be utilized as a therapeutic
elucidated, the JAK/STAT signaling cascade has been iden- target for the treatment of human diseases. Impor-
tied as a possible mediator of exercise-induced skeletal tantly, as maintenance of skeletal muscle is essential
muscle adaptation. Due to the range of cytokines and for healthy aging, our understanding of this pathway
growth factors that may regulate JAK/STAT signaling in in skeletal muscle needs to be increased if we want to
human skeletal muscle, it is difcult to discern a distinct develop novel therapies to combat age-related muscle
signaling cascade that may be occurring in response to disorders.
exercise. Additionally, different modes of exercise, and
exercise intensity, may elicit alternate signaling responses
of the JAK/STAT proteins and their activating ligands.
References
1. Boengler K et al (2008) The myocardial JAK/STAT pathway: from
Upstream of STATs, IL-6, LIF, and GH (growth hormone) protection to failure. Pharmacol Ther 120(2):172185
abundance increases immediately post exercise to 2. Spangenburg EE (2007) Suppressor of cytokine signaling, skeletal
facilitate muscle hypertrophy. Phosphorylation of JAK muscle, and chronic health conditions: the potential interactions.
and STAT occurs rapidly and transiently in response to Exerc Sport Sci Rev 35(3):156162
3. Trenerry MK, Della Gatta PA, Cameron-Smith D (2011) JAK/STAT
acute aerobic and resistance exercise [4]. The negative
signaling and human in vitro myogenesis. BMC Physiol 11(1):6
regulator SOCS3 is also upregulated following resistance 4. Trenerry MK et al (2010) Impact of resistance exercise training
and endurance exercise [2]. Signicantly, JAK/STAT on interleukin-6 and JAK/STAT in young men. Muscle Nerve
signaling does not appear to be inuenced by resistance 43(3):385392
training, as elevations in key molecules are preserved after 5. Trenerry MK et al (2008) Exercise-induced activation of STAT3
signaling is increased with age. Rejuvenation Res 11(4):717724
progressive resistance exercise training, further highlighting
their importance for effective skeletal muscle adaptation
and repair [4].

Aging Janus Kinases (JAK)


Aging is associated with higher levels of circulating
inammatory cytokines such as IL-6 and tumor necrosis JAK/STAT Pathway
498 J JNKs

Cross-References
JNKs Immune System
Inammation
The c-Jun N-terminal Kinases, (also stress-activated
phospho-kinases (SAPK)), are important proteins for sig-
nal transduction events, especially stress signals belonging
to the MAP kinase family. They are also called stress
kinases. Their name is derived from the ability to phos- Juvenile-Onset Diabetic
phorylate N-terminal amino acids from c-Jun. Myopathy
Diabetes Mellitus, Myopathy

J-Shaped Curve
The term J-curve is used in several different elds to
refer to a variety of unrelated J-shaped diagrams where
a curve initially falls, but then rises to higher than the
starting point.

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