The intracellular signaling pathways make possible a cell surface information transmission , most often from a receptor cell, to the cell nucleus where gene expression occurs is going to be modulated through a cascade of intracytoplasmic protein activation.
They are multiple and we will present in this article the most important, which are particularly involved in cell activation and expression of pro-inflammatory cytokines that play a critical role in rheumatism inflammatory. The intracellular signaling pathways described here relate to NF-κB (nuclear factor kappa B), MAP kinase activation pathways (MAPKs) and JAK / STATs.
The NF-κB signaling pathway
The nuclear factor NF-κB (Figure 1) is a family composed of 5 proteins fixing DNA and regulating the expression of a large number of genes involved in various biological functions such as immunity, inflammation, development and apoptosis.
They consist of homodimers and heterodimers which are sequestered in the absence of activation in the cytoplasm in combining with inhibitory proteins of NF-κB (IκB). IκB kinase (IKK) phosphorylates, ubiquitin and degrades IκB, which results in the release of NF-κB which enters the nucleus where it activates target genes. Gene transcription mediated by NF-κB is also regulated by post-transcriptional modifications. Activation of IKK depends on proteins adapters located upstream of the signaling channel, such as TRAF and RIP proteins.
Thus the signaling pathway of NF-estB consists of dimers NF-κB, IκB proteins, IKK complexes and proteins intracellular adapters, in particular from the TRAF family (TNF receptor associated factors).
The activation path MAP kinases (MAPK)
The pathway of MAP kinases (“mitogen activated protein kinases”) is one of the main routes of transmission of proliferation signals provided by growth factors such as NGF (“nerve growth factor”). This way involves, after activation of receptors and through adapter proteins, activation of a protein Ras, at the origin of the cascade of phosphorylation activities: MAP kinase kinase kinase (MKKK or MAP3K), MAP kinase kinase (MKK, MEKK or MAP2K) and MAP kinase (MAPK). A MAP3K which is activated by extracellular stimuli phosphorylates a MAP2K on its serine and threonine residues, then this MAP2K activates a MAP kinase through the phosphorylation of its serine and threonine residues. This last, translocated in the cell nucleus, phosphorylated then the transcription factors that activate transcription of all the genes responsible for the replication of DNA and the initiation of the cell cycle (DNA polymerases, cyclins, etc.). Thus, MAP kinases are proteins which have kinase activity which phosphorylates serine / threonines in response to extracellular stimuli such as mitogens and which thus regulate activities various cells such as gene expression, mitosis, cell differentiation, proliferation and survival and its corollary, apoptosis or programmed cell death. Six main groups of MAPKs have been identified in mammals:
1) Kinases regulated by an extracellular signal (ERK1, ERK2). ERK1 / 2 kinase pathway activation (also known as classic MAP kinases) is observed in response to growth factors or phorbol ester, and regulate cell proliferation and cell differentiation.
2) C-Jun N-terminal kinases (JNKs). They understand MAPK8, MAPK9 and MAPK10 and are also known as name of protein kinases associated with stress (SAPKs). They in particular activate the pro-inflammatory genes by allowing the binding of a cJun / c-Fos complex at the promoter level gene.
3) The p38 isoforms. There are several types: p38- α (MAPK14), p38-β (MAPK11), p38-γ (MAPK12 or ERK6) and p38-δ (MAPK13 or SAPK4). Signaling channels p38 and JNK are activated in response to stress stimuli such as cytokines, ultraviolet irradiation, shock thermal or osmotic and are involved in cell differentiation and apoptosis. Activation of MAPK11 results in increased production of TNFα by the macrophage stimulated by lipopolysaccharide (LPS).
4) ERK5 (MAPK7). It is a discovered kinase recently which is activated both by factors of growth and by stress and that participates in proliferation cellular.
5) ERK3 / 4. ERK3 (MAPK6) and ERK4 (MAPK4) are Atypical but structurally close MAPKs which have a SEG pattern in their activation loop and which differ only at their C-terminus. ERK3 and ERK4 are essentially cytoplasmic proteins which attach to and activate MK5 (PRAK, MAPKAP5). ERK3 is unstable, while ERK4 is relatively stable
6) ERK7 / 8 (MAPK15). This is a discovery MAPK recently behaving like atypical MAPKs and has a long C-terminal end similar to ERK3 and ERK4.
The signaling path JAK / STAT
The JAK / STAT signaling pathway participates in the regulation of cellular response to cytokines and factors growth. Following activation by a cytokine or a growth factor, the signaling pathway uses JAK proteins (Janus kinases) and STATs (Signal transducers and activators of transcription) to transmit the extracellular signal to the nucleus in which the activated STAT proteins modulate gene expression.
This signaling channel plays a critical role in cell proliferation and cell differentiation and apoptosis. She is particularly important in hematopoiesis. JAKs proteins that have tyrosine kinase activity bind on certain cytokine receptors. Binding the ligand to its receiver will activate JAK. The kinetic activity of JAK being increased will result in increased phosphorylation of tyrosine residues on the receptor and thus create sites of interaction with proteins which contain SH2 domains fixing phosphotyrosines. STAT proteins have SH2 domains capable of fixing these phosphotyrosine residues which are thus recruited on the receptors and are themselves phosphorylated at the level of their tyrosine residues by JAKs.
These phosphotyrosines will then serve as a fixing for SH2 domains of other STATs molecules, thus promoting their dimerization. Thus different STAT proteins can form homodimers or heterodimers. These dimers STATs thus activated will translocate to the cell nucleus and activate transcription of target genes . In addition, STATs can also be directly phosphorylated at the level of their tyrosine residues by tyrosine kinases present at the receptor level (eg EGF receptor or “Epidermal growth factor “) or by c-src-type tyrosine kinases. The JAK / STAT signaling channel is regulated in several levels. Cellular phosphatases can remove phosphates of cytokine receptors as well as STATS activated .
SOCS proteins have recently been identified (“Suppressors of cytokine signaling”) which inhibit the phosphorylation of STATs by fixing and blocking JAKs or while entering into competition with the STATs for the fixing sites phosphotyrosines at receptors cytokines. STATS are also negatively regulated by activated STAT inhibitor proteins (PIAS) that act at the nucleus.
PIAS1 and PIAS3 thus inhibit transcriptional activation mediated by STAT1 and STAT3 by fixing on them or blocking their access to the sequences that they recognize.
The intracellular signaling pathways, in particular of NF-κB, MAPKs and JAK / STATs play a critical role in numerous cellular functions such as proliferation, differentiation, apoptosis, inflammation and immunity. Their molecular understanding has come a long way since a few years and helps explain the mechanisms at the base of number of pathologies. We can also consider that in the near future they may be the target of new therapeutics, especially in the areas of inflammation, cancer and infectious diseases.