*3.2. TNFR2 Signaling Pathways*

Unlike TNFR1, TNFR2 does not have a DD, being unable to recruit TRADD [53]. Upon TNF-α binding, TNFR2 interacts directly with TRAF 1 or TRAF2, which recruits cIAP1 and 2, along with LUBAC [70,71]. Accordingly with the events triggered by TNFR1 signaling, the ubiquitin chains formed by LUBAC allow the recruitment of TAK1 and IKK complexes; therefore, activating the canonical NF-κB signaling pathway.

However, TNFR2 may also trigger non-canonical NF-κB signaling [72], by promoting activation of the NF-κB inducing kinase (NIK) [73]. In the absence of stimuli, NIK is ubiquitinated by intracellular TRAF/cIAPs complexes, and undergoes proteasomal degradation. However, upon TNF-α binding, the subsequent recruitment of these complexes by TNFRs, leads to NIK stabilization and activation. Activated NIK phosphorylates and induces the processing of p100, a protein that acts as an IκB-like molecule, which allows the nuclear translocation of p52/RelB [73]. This evidence confirms earlier studies that showed that the TNFR2 signaling involved in NF-kB activation occurs independently of TNFR1 signaling, which highlights distinct molecular pathways not shared with TNFR1 [74].

Furthermore, TNFR2 is able to activate JNK and protein kinase B (Akt) pathways [75,76]. TNFR2-mediated JNK activation seems to be TRAF2-dependent [76]. TNFR2 associates with apoptosis signal-regulating kinase-1 (ASK-1), an upstream MAPK critical for JNK activation [77]. TNFR2 mediated endothelial/epithelial protein tyrosine kinase (Etk) activation, subsequently stimulates phosphatidylinositol 3-kinase (PI3K) and its effector Akt, promoting pro-survival and reparative cascades [78]. These pathways are likely to be involved in the TNF-dependent activation of mesenchymal stem cells and T cells [44].

In endothelial cells, TNFR2 also signals through interferon regulatory factor-1 (IRF1), inducing interferon-β (IFN-β), promoting the transcription of inflammatory cytokines and monocytes recruitment during a TNF-induced inflammatory response [79].

TNFR2 can induce cell death indirectly by crosstalk with TNFR1. Depletion of TRAF2 by TNFR2 inhibits the NF-kB and MAPK signaling pathways mediated by TNFR1, favoring the formation of death complexes [80].

When TNFR1 and TNFR2 are co-expressed in the same cells, intracellular crosstalk between both signaling pathways seems to be mainly shaped by intracellular constraints, such as the availability of downstream effectors of each pathway, such as TRAF2 and ASK-1 [81,82]. However, there are other factors that contribute to the complexity of this cross-talk, such as the differential expression of both receptors in different cell types and the fact that the two signaling pathways are linked by positive and negative feedback mechanisms [44].
