Commentary Cell Science Reviews Vol 6 No 2 ISSN 1742-8130

PACS-2, at the cross roads of ER trafficking and TRAIL-induced apoptosis

Recombinant TRAIL (TNF-α Related Apoptosis Inducing Ligand) and agonistic monoclonal antibodies against its two death receptors, DR4 and DR5/KILLER, are currently in Phase I/II clinical trials for single or combination drug therapies for several kinds of cancer. While some of the existing basic data is being utilized in these clinical trials, novel insights into TRAIL signaling and its downstream effectors continue to emerge. A recent report in Molecular Cell indicates that TRAIL signaling is under the control of PACS-2, an unusual controller of ER trafficking. The findings suggest that PACS-2 becomes phosphorylated on Ser 437 by the activity of the pro-survival AKT kinase. The phosphorylated PACS-2, capped by 14-3-3 partners, ships cargo from the endoplasmic reticulum onwards and in this form cannot participate in apoptosis signaling. Upon initiation of TRAIL signaling, Ser 437 phosphorylation levels become inadequate, converting PACS-2 into an accomplice of the cellular killer protein BID. PACS-2 thus acts as a ‘jack of many trades’, as in its non-phosphorylated form it can chaperone full length BID to the mitochondrial outer membrane. It seems that mitochondria act as secondary posts for BID cleavage, possibly by cytoplasmic active caspase 8 or cathepsins, causing cytochrome c release and cell death.

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