THE SERINE THREONINE PHOSPHATASE INHIBITOR CALYCULIN-A INDUCES RAPID DEGRADATION OF I-KAPPA-B-BETA - REQUIREMENT OF BOTH THE N-TERMINAL ANDC-TERMINAL SEQUENCES/
Ew. Harhaj et Sc. Sun, THE SERINE THREONINE PHOSPHATASE INHIBITOR CALYCULIN-A INDUCES RAPID DEGRADATION OF I-KAPPA-B-BETA - REQUIREMENT OF BOTH THE N-TERMINAL ANDC-TERMINAL SEQUENCES/, The Journal of biological chemistry, 272(9), 1997, pp. 5409-5412
Signal-initiated activation of the transcription factor NF-kappa B is
mediated through proteolysis of its cytoplasmic inhibitory proteins I
kappa B alpha and I kappa B beta. While most NF-kappa B inducers trigg
er the degradation of I kappa B alpha, only certain stimuli are able t
o induce the degradation of I kappa B beta. The degradation of I kappa
B alpha is targeted by its site-specific phosphorylations, although t
he mechanism underlying the degradation of I kappa B beta remains elus
ive. In the present study, we have analyzed the effect of phosphatase
inhibitors on the proteolysis of I kappa B beta. We show that the seri
ne/threonine phosphatase inhibitor calyculin A induces the hyperphosph
orylation and subsequent degradation of I kappa B beta in both human J
urkat T cells and the murine 70Z-3 preB cells, which is associated wit
h the nuclear expression of active NF-kappa B. The calyculin A-mediate
d degradation of I kappa B beta is further enhanced by the cytokine tu
mor necrosis factor-alpha (TNF-alpha), although TNF-alpha alone is una
ble to induce the degradation of I kappa B beta. Mutational analyses h
ave revealed that the inducible degradation of I kappa B beta induced
by calyculin A, and TNF-alpha requires two N-terminal serines (serines
19 and 23) that are homologous to the inducible phosphorylation sites
present in I kappa B alpha. Furthermore, the C-terminal 51 amino acid
residues, which are rich in serines and aspartic acids, are also requ
ired for the inducible degradation of I kappa B beta. These results su
ggest that the degradation signal of I kappa B beta may be controlled
by the opposing actions of protein kinases and phosphatases and that b
oth the N- and C-terminal sequences of I kappa B beta are required for
the inducible degradation of this NF-kappa B inhibitor.