The activation of the extracellular signal-regulated kinases (ERKs) by tumour 
necrosis factor-alpha (TNF) receptors (TNFRs) is an integral part of the 
cytokine's pleiotropic cellular responses. Here we report differences in the 
caspase sensitivity and TNFR subtype activation of members of the ERK family. 
Inhibition in HeLa cells of caspase function by pharmacological inhibitors or 
the expression of CrmA (cytokine response modifier A), a viral modifier protein, 
blocks TNF-induced apoptosis or caspase-dependent protein kinase Cdelta and 
poly(ADP-ribose) polymerase protein degradation. TNFR1- or TNFR2-stimulated 
c-Jun N-terminal kinase (JNK) activity was attenuated in cells in which caspase 
activity was inhibited either by pharmacological blockers or CrmA expression. 
Both TNFR1- and TNFR2-stimulated JNK activity was caspase-sensitive; however, 
only TNFR1 was capable of stimulating p42/44 mitogen-activated protein kinase 
(MAPK) and p38 MAPK activities. TNFR1-stimulated p42/44 MAPK and p38 MAPK 
activities were insensitive to pharmacological caspase inhibition or CrmA. These 
findings were supported when measuring TNF-induced cytosolic phospholipase A(2) 
activation, which is a downstream target for MAPK and p38 MAPK. Profiling 
caspase enzymes activated by TNF in HeLa cells showed sequential caspase-8, -3, 
-7, -6 and -9 activation, with their inhibition characteristics suggesting a 
role for caspase-3 and/or caspase-6 in modulating JNK activity. Taken together 
these results show delineated ERK-activation pathways employed by TNFR subtypes.