Transcript Prezentace aplikace PowerPoint

MITOGEN-ACTIVATED PROTEIN
KINASE (MAPK) SIGNAL
TRANSDUCTION PATHWAY
Jiří Wilhelm
MAP kinases are intermediates in signal transduction
pathways that are initiated by many types of surface
receptors
The targets of MAPK are located within many
cellular compartments
MAPK provide a physical link in the signal transduction
pathway from the cytoplasm to the nucleus
(these are relatively novel and not well desccribed)
Regulation of gene expression through MAPK
signaling pathways
- phosphorylation of transcription factors, thereby enhancing
their activity
- negatively regulated transcription factors by promoting their
retention in the cytoplasm upon phosphorylation; active
dephosphorylation of these factors is needed for their
migration to the nucleus
- translational regulation
- regulation of protein degradation; phosphorylation of
transcription factors inhibits their ubiquitination and thus
their degradation by the proteasome
Recognition of a reaction partner by a
kinase or phosphatase
NONRECEPTOR TYROSINE KINASES
These are cytoplasmic enzymes that play roles in many
signal transduction pathways.
The term “nonreceptor“ means they lack a transmembrane
domain, although they are associated with cell membranes.
They are grouped into families:
Src
Syk
Abl
Fak
Tec/Btk
-Src
was the first protein kinase with identified role in
malignant transformation. Rous’s Sarcoma Virus
contained src gene coding tyrosine kinase. The viral
gene is now called v-src, while the cellular protooncogene is labeled c-src, or just src.
Src family kinases function in development and in
hematopoietic cells.
They are activated by integrin ligands, cytokines, and
stimuli that act via immunoreceptors.
N-terminal domain of Src kinases is modified by
N-myristoylation, which enables membrane anchoring.
Other domains include SH3 domain, SH2 domain and
kinase domain.
There are 2 principal conformational states, indicated as
“on” and “off”.
In the “off” state SH2 and SH3 domains are engaged in
intramolecular interaction and the kinase domain is inactive.
In the “on” state, the intramolecular interactions are absent,
the kinase domain is active, and the SH2 and SH3 domains
are accessible for binding other proteins. Thus, in this state
Src can also act as a scaffold for other proteins.
In the cell, Src kinases are regulated by the balance of kinases
and phosphatases acting at both inhibitory and activating
phosphorylation sites, and by proteins that bind to their
SH2 and SH3 domains.
- Syk (spleen tyrosine kinase)
family of protein kinases have essential roles in the function
and development of T cells, B cells, mast cells, monocytes/
macrophages, and the lymphatic system.
- Tec
family of PTKs is primarily found in hematopoietic cells. It
plays a critical part in T cell or B cell receptor signaling and
is also involved in cytokine receptor signaling. These PTKs
are functionally interconnected with Src kinases in cell
signaling.
SIGNALING USING PHOSPHOINOSITIDES
Phosphorylated PKC is localized to the cytosol, where it is
maintained inactive, because the pseudosubstrate sequence
occupies the substrate-binding cavity. The membrane-bound
species adopt the active conformation by removal of the
pseudo substrate.
Correct subcellular location is essential for normal signaling.
An abundance of scafold protein that tether PKC near its
substrates, activators, and regulatory proteins is needed.
Down-regulation involves dephosphorylation of activated
PKC, followed by ubiquitination and proteolysis.
The chaperone HSP70 protects PKC from down-regulation.
PKC phosphorylates many substrates, including membrane
proteins, cytoskeletal proteins, cytosolic and nuclear proteins.
Generally, animals deficient in PKC isozymes are deficient in
adaptive responses.
Intracellular signaling cascades are the main routes of communication between the
Plasma membrane and regulatory targets in various intracellular compartments.
Sequential activation of Kinases is a common mechanism of signal transduction in many
cellular processes. During the past decade, several related intracellular signaling
cascades have been elucidated, which are collectively known as MAPK (MitogenActivated Protein Kinase) signaling cascades. The MAPKs are a group of protein
Serine/threonine Kinases that are activated in response to a variety of extracellular
stimuli and mediate signal transduction from the cell surface to the nucleus. In
combination with several other signaling pathways, they can differentially alter
phosphorylation status of numerous proteins, including Transcription Factors,
Cytoskeletal proteins, Kinases and other Enzymes, and greatly influence Gene
Expression, Metabolism, Cell Division, Cell Morphology and Cell Survival. Furthermore,
epigenetic aberrations of these enzymes or of the signaling cascades that regulate them
have been implicated in a variety of human diseases including Cancer, Inflammation and
Cardiovascular disease. There are four major groups of MAPKs in mammalian cells-the
ERKs (Extracellular signal-Regulated Kinases), the p38MAPKs, the JNKs (c-Jun NH2terminal Kinases) and the ERK5 (Extracellular signal-Regulated Kinase-5) or BMK
cascades. These MAPKs are activated by dual phosphorylation at the tripeptide motif ThrXaa-Tyr. The sequence of this tripeptide motif is different in each group of MAPKs: ERK
(Thr-Glu-Tyr); p38 (Thr-Gly-Tyr); and JNK (Thr-Pro-Tyr). Each MAPK pathway contains a
three-tiered kinase cascade comprising a MAPKKK/MAP3K/MEKK/MKKK (MAP Kinase
Kinase Kinase), a MAPKK/MAP2K/MEK/MKK (MAP Kinase Kinase) and the MAPK. This
three-tier module mediates ultrasensitive switch-like responses to stimuli. Frequently, a
MAPKKKK, MAP4K or MKKKK (MAPKKK Kinase) activates the MAPKKK. The MAPKKKs then
phosphorylates a dual-specificity protein kinase MAPKK, which in turn phosphorylates
the MAPK (Ref.1 & 2).
ERK, the most widely studied MAPK cascade, have been established as a
major participant in the regulation of cell growth and differentiation, but
when improperly activated contribute to malignant transformation. ERK1
and ERK2 form the central component in the ERK cascade. The ERK
signaling cascade is activated by a wide variety of receptors involved in
growth and differentiation including GPCRs (G-Protein Coupled Receptors),
RTKs (Receptor Tyrosine Kinases), Integrins, and Ion Channels. A general
activation scheme involves the activation of RTKs by Growth Factors, such
as EGF (Epidermal Growth Factor). The subsequent auto-phosphorylation
of the cytoplasmic tails of the receptor on tyrosine leads to the tyrosine
phosphorylation of the adapter protein SHC. SHC can then recruit the GRB2
(Growth Factor Receptor Bound Protein-2)-SOS (Son of Sevenless protein)
complex to the membrane via the SH2 domain of GRB2 binding to the
phosphotyrosine on SHC. SOS, a GEF for Ras, can then exchange the GDP
bound to Ras to GTP. Once Ras binds GTP, it can then recruit the
Serine/threonine kinase Raf to the membrane. When Raf translocate to the
membrane, it becomes activated and then phosphorylates the dual
specificity kinases MKK1 and MKK2. The activated MKKs phosphorylate
ERK1/ERK2 on Threonine183 and Tyrosine185 (at the TEY motif) (Ref.3).
GPCR also play an important role in activation of ERKs. When the GPCR
becomes activated by Ligands such as Neurotransmitters, Cytokines etc., it
leads to the exchange of GDP for GTP on the GN-Alpha (Guanine
Nucleotide-Binding Protein-Alpha) subunit. Upon activation, GN-AlphaI
(Guanine Nucleotide-Binding Protein-Alpha-I) or GN-AlphaQ (Guanine
Nucleotide-Binding Protein-Alpha-Q) subunits are separated from GN-Beta
(Guanine Nucleotide-Binding Protein-Beta) and GN-Gamma (Guanine
Nucleotide-Binding Protein-Gamma) subunits and are converted to their
GTP bound states that exhibit distinctive regulatory features on the nine
tmACs (Transmembrane Adenylate Cyclases) in order to regulate
intracellular cAMP (Cyclic Adenosine 3',5'-monophosphate) levels.
cAMP activate Rap1A (Ras-Related Protein-1A) and Rap1B (Ras-Related
Protein Rap1B) through EPAC (Exchange Protein Activated by cAMP)dependent pathway. cAMP activates cAMP-GEFI (cAMP-Regulated Guanine
Nucleotide Exchange Factor-I)/EPAC1 and cAMP-GEFII (cAMP-Regulated
Guanine Nucleotide Exchange Factor-II)/EPAC2 that in turn activate Rap1A
and Rap1B, respectively. Rap1A and Rap1B then forms an active complex
with BRaf (v-Raf Murine Sarcoma Viral Oncogene Homolog-B1) for MEK1/2
activation finally resulting in ERK1/2 activation. cAMP may also activate
PKA (Protein Kinase-A), which may further activate Rap and thus BRaf. On
the other hand, PKA also inactivates C-Raf. GN-Alpha also directly activates
PLC (Phospholipase-C) which further activates PKC (Protein Kinase-C) via
DAG (Diacylglycerol). PKC further activates Raf and thus ERK. A new
mechanism has recently been identified that regulates MEK1-ERK
interactions and is dependent on Rac and PAK (p21-Activated Kinase).
Integrins also play an important role in regulating the efficiency of the
RTK/Ras/ERK pathway. FAK (Focal Adhesion Kinase) is a major
nonreceptor tyrosine kinase activated after Integrin-mediated adhesion to
ECM (Extracellular Matrix) proteins such as FN (Fibronectin). Interaction
between FAK and the cytoplasmic tail of Beta1 Integrins results in
autophosphorylation of FAK tyrosine 397 (FAK pY397) that can lead to
stimulation of a cell-signaling cascade that ultimately activates the
Ras/MAPK/ERK pathway. In addition to FAK, members of the Src family of
nonreceptor protein-tyrosine kinases also associate with Focal Adhesions
and are involved in Integrin signaling.
Interestingly, Src and FAK appear to function in association with each
other as a result of the binding of the Src SH2 domain to an
autophosphorylation site of FAK. Src then phosphorylates additional sites
on FAK. Tyrosine phosphorylation of FAK creates binding sites for the SH2
domains of other downstream signaling molecules, including PI3K
(Phosphatidylinositol 3-Kinase) and Rac. A key target of Rac is the proteinserine/threonine kinase PAK. Rac and CDC42 (Cell Division Cycle-42) can
synergize with Raf to promote activation of the ERKs through mechanisms
involving PAK1 phosphorylation of the MEK1 proline-rich sequence and
PAK3 phosphorylation of Raf1. PAK3 can phosphorylate Raf1, enhancing
Raf1 activation. Raf1 finally activates ERK1/2 via MEK1/2. ERK once
activated translocates to the nucleus to phosphorylate and activate several
nuclear targets. The major target of activated ERKs is RSK (90 kDa
Ribosomal protein S6 Kinase). Active RSKs appear to play a major role in
transcriptional regulation, translocating to the nucleus and
phosphorylating such factors as the product of proto-oncogene c-Fos at
Ser362, SRF (Serum Response Factor) at Ser103, and CREB (Cyclic AMP
Response Element-Binding protein) at Ser133. ERK also translocates to the
nucleus to phosphorylate transcription factor Elk1 (on Serine383 and
Serine389). Another important target of ERK is NF-KappaB (Nuclear FactorKappaB), which binds to its consensus sequence (5'-GGGACTTTC-3') and
positively regulates the transcription of genes involved in immune and
inflammatory responses, cell growth control, and apoptosis. Other nuclear
targets of ERK include the MSKs (Mitogen- and Stress-activated protein
Kinases), CREB, c-Myc, HSF1 (Heat-Shock Factor-1), Paxillin and many
more transcription factors (Ref.4, 5 & 6).
Recently, another related kinase, ERK3, a nuclear protein kinase, has been cloned and is
reported to exhibit about 50% homology to ERK1/ERK2 within its catalytic domain.
However, it does not phosphorylate any typical ERK substrates. The phosphorylation site
motif in the activation loop of ERK3 has a single phosphorylation site located at
Serine189. Another member of ERK family is the ERK5 that contains at least ten
consensus sites for MAPK phosphorylation and may be associated with keeping ERK5 in
high active state. ERK5 can be activated by proliferative stimuli such as EGF, Serum,
Lysophosphatidic acid, Neurotrophins and Phorbol ester, as well as by stress stimuli such
as Sorbitol, H2O2, and UV irradiation. WNK1 (WNK Lysine deficient protein Kinase-1) is
required for activation of ERK5 by EGF. MEK5 (MAPK/ERK Kinase-5) and MEKK2/3
(MAP/ERK Kinase Kinase-2/3) acts as upstream regulators of ERK5. The known ERK5
substrates include the MEF2 (Myocyte Enhance Factor-2) family members, MEF2A, C and
D, and the ETS-like transcription factor SAP1A (Signaling lymphocytic Activation
molecule associated Protein-1A) (Ref.7 & 8).
The second most widely studied MAPK cascade is the JNK/SAPK (Stress Activated
Protein Kinase). The JNKs/ SAPKs are encoded by at least three genes: SAPKAlpha/JNK2, SAPK-Beta/JNK3, and SAPK-Gamma/JNK1. This cascade is activated
following exposure to UV radiation, Heat shock, or Inflammatory Cytokines. Directly
upstream of JNK, at the MAPKK level, there are two dual specificity kinases that
phosphorylate and activate JNK at Serine and threonine residues. These kinases are
MKK4 (MAPK Kinase-4), and MKK7 (MAPK Kinase-4). These proteins are activated, in
turn, by the upstream MAP3K: MEKKs (MAPK/ERK Kinase Kinases), MLK2/3 (Mixed
Lineage Kinase-2/3), TAK1 (TGF-Beta-Activated Kinase-1), TPL2 (Tumor Progression
Locus-2), ZPK (Zipper Protein Kinase), and ASK1 (Apoptosis Signal-regulating Kinase-1).
Some other MAP3Ks have also been identified, whose functions are not known. These
included MAP3K6, MLK1 (Mixed Lineage Kinase-1) and LZK (Leucine Zipper-bearing
Kinase).
The Rho family GTPases, CDC42 and Rac initiate a cascade leading to
JNK/SAPK, presumably by binding and activating the protein kinase PAK, a
kinase that phosphorylates and promotes activation of MEKK1. CDC42 can
also be activated by GPCR. Stimulation of GPCRs coupled to the GN-AlphaS
subunit of trimeric G-proteins, induces production of cAMP and activation
of PKA. Activation of PKA enhances the activity of CDC42 and thus plays an
important role in activation of JNKs. The activation of JNK by Cytokine
receptors appears to be mediated by the TRAF (TNF Receptor-Associated
Factor) group of Adaptor proteins. Activation of the TNFR (Tumor necrosis
Factor Receptor) leads to recruitment of TRAF2 (TNF Receptor-Associated
Factor-2), which is required for JNK activation. This Adaptor protein
(TRADD (Tumor Necrosis Factor Receptor-1-Associated Death Domain
Protein), RIP (Receptor-Interacting Protein), Daxx) has been reported to
bind MEKK1 and ASK1. The activated JNK/SAPKs translocate to the nucleus
where they phosphorylate transcription factors such as c-Jun, c-Fos, DPC4
(Deleted in Pancreatic Carcinoma 4), p53, ATF2 (Activating Transcription
Factor-2), NFAT4 (Nuclear Factor of Activated T-Cell-4), NFAT1 (Nuclear
Factor of Activated T-Cell-1), STAT1 (Signal Transducers and Activators of
Transcription-1), HSF1, SHC and Bcl2 (B-Cell CLL/Lymphoma-2). JNKregulated transcription factors help to regulate gene expression in
response to a variety of cellular stimuli, including stress events, Growth
Factors and Cytokines. Activation of the JNK signaling cascade generally
results in Apoptosis, although it has also been shown to promote cell
survival under certain conditions and has important roles in determining
cell fate during metazoan development as well as involvement in
tumorigenesis and inflammation (Ref.9, 10 & 11).
The p38 kinase is most well-characterized member of the MAP kinase family. It shares
about 50% homology with the ERKs. Four p38 MAPKs have been cloned so far in higher
eukaryotes: p38-Alpha/XMpk2/CSBP, p38-Beta/p38-Beta22, p38-Gamma/SAPK3/ERK6,
and p38-Delta/SAPK4. The mammalian p38 MAPK families are activated by cellular
stress including UV irradiation, Heat shock, High osmotic stress, Lipopolysaccharide,
Protein synthesis inhibitors, Proinflammatory Cytokines (such as IL-1 (Interleukin-1)
and TNF-Alpha (Tumor Necrosis Factor-Alpha)) and certain Mitogens. The upstream
MAPK cascade in p38 activation includes MAPKKKs such as ASK1, MEKK1, MEKK 4, MLK2
and 3, DLK (Dual Leucine Zipper Kinase), TPL2 (Tumor Progression Locus-2), TAK1 and
TAO1/TAO2, which phosphorylate and activate MKK3 and MKK6, which in turn
phosphorylate and activate p38. Proinflammatory cytokines such as IL and TNF are the
main stimulator of p38. IL-1 signaling is known to involve PI3K, p38MAPK and ERK. After
IL-1 is bound to its receptor IL-1R (IL-1 Receptor), a complex is formed between the
Type-1 Receptor and the receptor accessory protein. The cytosolic proteins MyD88
(Myeloid Differentiation primary response gene-88) and TollIP (Toll-Interacting Protein)
are recruited to this complex, where they function as adaptors, recruiting IRAK1 (IL-1
Receptor-Associated Kinase-1) in turn. IRAK1, a serine-threonine kinase, activates and
recruits TRAF6 (TNF Receptor-Associated Factors-6) to the IL-1 receptor complex.
Eventually, phosphorylated IRAK is ubiquitinated and degraded. TRAF6 signals through
the TAB1 (TAK1 Binding Protein-1)/TAK1 (TGF-Beta-Activating Kinase-1) kinases to
activate MKKs, which further activates p38MAPK (Ref.12).
TNF also stimulate p38 signaling. Binding of TNFR1 to TNF-Alpha results in
conformational changes in the receptor's intracellular domain, resulting in rapid
recruitment of several cytoplasmic death domain-containing adapter proteins via
homophilic interaction with the death domain of the receptor. The first adaptor recruited
to the clustered receptor is the TNFR-associated protein with death domain, which
functions as a docking protein for several signaling molecules, such as FADD (FasAssociated protein with Death Domain), TRADD, Daxx, TRAF2 and RIP. RIP associates
with TRAF2 to generate MEKK4 and ASK1. Both MEKK4 and ASK1 activates p38MAPKs by
activating MKK3 and MKK6. Besides, p38 can also be activated by GPCRs and numerous
physical and chemical stresses, including hormones, UV irradiation, ischemia, osmotic
shock and heat shock. G-proteins activate p38 via PKA or PKC, whereas stress activates
p38 via Rac and CDC42. Following its activation, p38 translocates to the nucleus and
phosphoryates ATF2. Another known target of p38 is MAPKAPK2 (MAPK-Activated
Protein Kinase-2) that is involved in the phosphorylation and activation of heat-shock
proteins. Other transcription factors affected by the p38 family include STAT1 (Signal
Transducers and Activators of Transcription-1), Max/Myc complexes, Elk1 and CREB
through the activation of MSK1 (Mitogen- and Stress-Activated Kinase-1). The p38
subfamily is also involved in affecting Cell Motility, Transcription and Chromatin
Remodeling. Other substrates of the p38 signaling pathway include CHOP (C/EBPHomologous Protein) for regulation of gene expression, as well as MNK1 (MAPKInteracting Kinase-1). p38 MAPK is a crucial mediator in the NF-kappaB-dependent gene
activation induced by TNF (Ref.13, 14 & 15).
The mammalian MAPK signaling system employ scaffold proteins, in part, to organize the
MAPK signaling components into functional MAPK modules, thereby enabling the efficient
activation of specific MAPK pathways. The ERK scaffold protein KSR (Kinase Suppressor
of Ras) binds ERK, its direct activator MEK and Raf. A second targeting protein, p14,
targets ERK2 to an endosomal location through its interaction with MP1 (MAPKK1Interacting Protein-1), an adaptor protein that binds MEK and ERK. In addition, MEKK1
(MAP/ERK Kinase Kinase-1) can serve both as a scaffold and as MAPKKK, interacting
specifically with MAPKK and MAPK. Multidomain protein Posh (Plenty of SH3s) acts as a
scaffold for the JNK pathway. Posh binds MLKs both in vivo and in vitro, and complexes
with MKKs 4 and 7 and with JNKs. The JNK MAPK modules are also regulated by a JIP1
(JNK Interacting Protein-1), JIP2 (JNK Interacting Protein-2), JIP3 (JNK Interacting
Protein-3), JIP4 (JNK Interacting Protein-4), Beta-Arrestin-2, Filamin and CrkII. There is
increasing evidence that the three well-characterized members of the MAPK family,
ERK1/2, JNK/SAPK and p38 play an important role in regulation of proliferation in
mammalian cells by sharing substrate and cross-cascade interaction. MAPK pathways are
involved in many pathological conditions, including cancer and other diseases. Therefore,
a better understanding of the relationship between MAP kinase signal transduction
system and the regulation of cell proliferation is essential for the rational design of novel
pharmacotherapeutic approaches (Ref.16 & 17).
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