Figure 8.

Working model of positive NF‐κB/Notch signal regulation by GIT1. GIT1 interacts with NEMO via their mutual CC2 structures and enhances NEMO affinity for K63‐linked ubiquitination of RIP1 induced by TRAF2 (Figure 8). It leads to phosphorylation of the IKKα/β/NEMO complex and facilitates activation of the canonical NF‐κB signal, but not the non‐canonical signal. It regulates the Notch signalling by increasing translocation of NICD into the nucleus and subsequently leading to interaction of NICD and RBP‐jк, requiring cleavage from the Notch molecules to be induced by γ‐secretase and blocked by DAPT. Therefore, endogenous GIT1 enhances nuclear import of the canonical NF‐κB subunits P65 and P50 and NICD, leading expression of the downstream target genes of the NF‐κB/Notch signal, such as VEGF and other angiogenic factors in BMSCs, during the early stages of fracture healing