Fig 2: Model of F. tularnesis anti-apoptosis signaling in neutrophils. Signaling via TLR2 heterodimers and phagocytic receptors engage mutliple survival signaling pathways. MEK and ERK promote survival in some systems but not during F. tularensis infection. p38 MAPK and PI3Kα are required for extended neutrophil survival in our system and both may act via NF-κB, leading to expression of prosurvival factors, including XIAP. p38 MAPK may also be upstream of MK2 and GSK3β, and our recent data demonstrate that glycolysis and glycogen play key roles in neutrophil survival during F. tularensis infection and glycolysis pathway enzymes, including PFKFB3 are induced. At the same time, both PI3K and p38 are linked to inhibition of the proapoptosis factors BAD and BAX that disrupt mitochondrial integrity to initate the intrinsic appoptosis pathway. Having excluded a role for AKT, we speculate that other effectors of PI3K, such as PDK-1 and PKCζ may be involved, but this remains to be determined. Blue symbols, prosurvival enzymes with roles in other systems. Green symbols, molecular and pathways required for PMN survival during LVS infection. Red, proapoptosis factors. Grey, signaling intermediates not yet tested in our system.

Fig 3: Detection of expression of PI3K‐AKT pathway related proteins in RAW264.7 cells induced by MG‐132 when treated with different concentrations of SBP. GAPDH was used as the reference gene

Fig 4: PI3K signaling and stemness scores, but not PIK3CA genotype, are prognostic in ER+ breast cancer.Pan-breast cancer patient survival in METABRIC, as a function of PI3K signaling (A) or stemness (B) score. Survival analysis in estrogen receptor (ER)-positive breast cancer patients, as a function of PI3K signaling (C) or stemness (D) score. Low, intermediate and high classifications represent the bottom quartile, the interquartile range and the top quartile of the respective scores. (E) and (D) represent pan- and ER-positive breast cancer patient (METABRIC) survival, respectively, as a function of binary PIK3CA genotype. The mutant genotype captures only cases with activating missense mutations. The sample size for each panel and subgroup is indicated, and p-values were calculated using a log-rank test. The 95% confidence intervals are indicated by shading.

Fig 5: Model summarizes the contribution of defective NHEJ to PTEN DNA damage signalling and suppression of p53-mediated GBM formation and drug-resistant survival.PTEN is a sensor that is induced as an upstream factor of DNA damage response and repair pathways. Under normal physiologic conditions, in response to DSBs, active PTEN dimers accumulate in the nucleus and activate the available DNA repair pathways, particularly NHEJ. DSBs that progress with p53 loss are accumulated further in NHEJ-deficient cells. DNA damage induced under these conditions results in constitutive activation of CK2 that is enforced in the combined NHEJ- and p53-deficient setting that inactivates and retain PTEN predominantly in its monomeric inactive state. Cells lacking active dimeric PTEN are unable to mount a DNA damage response and activate repair pathways, and constitutively activate PI3K/AKT signalling that promotes the progression of oncogenic lesions in GBM pathogenesis. Blocking the formation of the inactive p-PTEN enzyme, by restraining CK2 in the presence of DNA-damaging agents, represents a potential therapeutic strategy that suppressed resistance to genotoxic stress and GBM survival.