Hi Ahmed:

I believe ER stress pathway, which has been shown by some researches to be mediated by caspase-12 activation (although still controversial), is still intrinsic and ends up in casp-3 activation.

To my best knowledge, there are three main caspase groups:

1-initiators: 2,8,9,10

2-executioners: 3,6,7

3-inflammatory: 1,4,5,11

And the role of casp-12 has not been fully supported in humans as to be involved in apoptosis, but apparently it has some functions in inflammatory responses. And also, it has been shown that following ER stress, increase in Ca2+ and calpains release from ER leads to mitochondrial transformation, Bid cleavage and caspase-3 activation supporting an intrinsic pathway, but whether casp-12 is also involved has not been fully elucidated (as far as I know!).

Thank you Dr.Abdi and Dr.Hamza for your kind responses, for Dr.Abdi the end with caspase 3 is for both interensic and externsic pathways so it will not be problem if ER pathway shared the execution phase with them, and for Dr.Hamza, in human cell lines caspase 12 will be activated in ER pathway of apoptosis as described in many researches.

For me I think as much as their is different cascade of caspases initiated we should consider it as a different pathway, simply it is different path with different caspases, right?

Hi again Ahmed:

I still persist that ER stress pathway cannot (or may not) be regarded as a separate pathway in apoptosis!!!!!!!!!, indeed it may involve multiple pathways, as there are strong literature proofs that ER activation really affects mitochondrial transformation, cytochrome-C release, apoptososme, blablabla....and this indicates its contribution to intrinsic pathway. So it would not be unexpected to imagine that ER stress pathway triggering may be a prerequisite for mitochondrial pathway (intrinsic) of apoptosis (this may not apply to all stimuli). Still some people showed it would also work through the extrinsic (receptor-mediated) pathway mediated by casp-8 activation. Further, recent work indicates ER stress could trigger p53 pathway activating it's downstream targets like PUMA and Noxa which impinge on mitochondrial pathway (see attachment). I am not sure if you can find any evidence supporting direct interaction of casp-12 with casp-3 leading to activation of the latter, in this link (http://www.plosone.org/article/info:doi/10.1371/journal.pone.0028531), people show activation of casp-12, casp-9 and casp-3 at the same time and indicate pro-cas-9 as a substrate for casp-12. I also think that some researchers who claim cas-12 mediates their apoptotic observations, should realize that this could be mediated by some inflammatory cytokines which trigger apoptosis by themselves. Finally there are some nice reports that ER stress pathway could trigger apoptosis through caspase-independent pathways.