The effect of tumor necrosis factor receptor 1 of SRC-homology 3 domain on signal transduction

TNF-α is a pleitropic cytokine and shows its biological function by binding to its receptors TNFR1 and TNFR2. While TNFR1 induces apoptosis by activation of caspase-8 via the "death domain", it also activates enzymes such as IKKα/β, MKK3/6, MKK4/7 by activation of TAK1. While activation of IKKα/β induces NF-kB, activations of MKK3/6 and MKK4/7 induces activations of p38 and JNK kinases, respectively it is not known how ERK1/2 and AKT activation are achieved in TNFR signalling pathway. Assuming that these two enzymes can act on Grb2-Ras or SRC-Ras pathways, we thought the binding sites of these adapters may be present on the TNFR1. A proline-rich PPAP region, "P448PAP451", a binding site for proteins containing the SH3 domain very close to the C-terminus, was discovered in the translation map of the TNFR1. We wanted to determine whether this region has a role in the TNFR1 signal transduction mechanism, and whether the TNFR1 receptor in the presence of TNF-α initiates signal transduction over the SH3 domain.