It is therefore paradoxical that SD pathways are poorly conserved, with master SD (MSD) genes at the top of the pathway differing between closely related species and even variable within species (Bull 1983; Wilkins 1995; Pomiankowski et al. 2004; Beukeboom and Perrin 2014).
These findings are in contrast to our previous observation that sorafenib induces paradoxical ERK signalling pathway in gastric carcinoma through upregulation of p-c-Raf Ser338 (Yang et al, 2009).
The results revealed that our compounds inhibited the proliferation of melanoma A375 cells (B-RafV600E) through ERK pathway, without paradoxical activation of ERK in melanoma SK-MEL-2 cells (B-RafWT).
Treatment of the DeltacnaA and DeltacrzA strains, harboring gene deletions of the calcineurin A subunit and the calcineurin-dependent transcription factor, respectively, with high concentrations of caspofungin revealed that the A. fumigatus paradoxical effect is calcineurin pathway dependent.
The UPR pathway elicits paradoxical outputs, inducing cytoprotective functions that reestablish homeostasis and cytodestructive functions that promote apoptosis, which is initially an effective means to eliminate a minority of cells that cannot recover from ER stress and protect the organism from damage induced by ER stress (Tabas and Ron, 2011; Iurlaro and Munoz-Pinedo 2016).
A phenotypically similar Marfan-like syndrome is caused by loss of function mutations in TGFβ receptors 1 or 2 [10]–[12], which nevertheless result in a paradoxical activation of the pathway and nuclear accumulation of pSmad2 [10].
Further common to both models is the concept that paradoxical activation of the pathway can only happen at low inhibitor concentration [92,107,108,110].
The immune-activating effects mediated by PLX4032 can be explained by the paradoxical activation of MAPK pathway in T-cells that are wildtype for BRAF, while the immune response mediated by PLX3397 is explained by the depletion of an immunosuppressive environment.
Inhibition of mTORC1, but not mTORC2, can cause paradoxical reactivation of the PI3K pathway through the alleviation of feedback loops dependent on S6K. 10 Pinhibitorstors, which target the pathway upstream of mTORC1, may therefore show utility in contexts in which mTORC1 inhibitors are unsuccessful or no longer effective.
