Regulation of interleukin receptor-associated kinase (IRAK) phosphorylation and signaling by iota protein kinase C
Regulation of interleukin receptor-associated kinase (IRAK) phosphorylation and signaling by iota protein kinase C
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DOI：
10.1074/jbc.c300431200
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发表时间：
2004-02-06
影响因子：
4.8
通讯作者：
Wooten, MW
中科院分区：
文献类型：
--
作者：
Mamidipudi, V;Lin, CR;Wooten, MW
我们之前已经证明，白细胞介素-1 （IL-1）受体相关激酶（IRAK）的活性是神经生长因子（NGF）诱导的NF-kappaB激活和细胞存活所必需的（2002）。化学，277,28010-28018)。本研究表明，NGF诱导IRAK与非典型蛋白激酶C - iota （PKC）共结合，而PKC - iota则与IRAK结合。IRAK复合体被募集到p75神经营养因子受体。IRAK对受体的招募依赖于iota PKC的活性。此外，转染激酶死亡的PKC阻断了NGF-和il -1诱导的IRAK激活和NF-kappaB的活性。因此，在kappaB通路中，PKC位于IRAK的上游。通过检查IRAK的初级结构，我们确定了三个假定的PKC磷酸化位点；iota PKC在Thr（66）的死亡结构域选择性磷酸化肽1 (R (T) under bar AS)，这在所有IRAK家族成员中高度保守。Thr（66）对Ala的突变破坏了IRAK的自激酶活性，降低了其与iota PKC的关联，但不会导致NGF-和il -1诱导的NF-kappaB活化受损。这些发现揭示了IRAK调控kappaB通路的潜在机制，并揭示了IRAK是iota PKC的底物。
We have previously shown that the activity of the interleukin-1 (IL-1) receptor-associated kinase (IRAK) is required for nerve growth factor (NGF)-induced activation of NF-kappaB and cell survival ((2002) J. Biol. Chem. 277, 28010-28018). Herein we demonstrate that NGF induces co-association of IRAK with atypical protein kinase C iota (PKC) and that the iota PKC.IRAK complex is recruited to the p75 neurotrophin receptor. Recruitment of IRAK to the receptor was dependent upon the activity of the iota PKC. Moreover, transfection of kinase-dead iota PKC blocked both NGF- and IL-1-induced IRAK activation and the activity of NF-kappaB. Hence, iota PKC lies upstream of IRAK in the kappaB pathway. Examining the primary structure of IRAK, we identified three putative PKC phosphorylation sites; iota PKC selectively phosphorylated peptide 1 (R (T) under bar AS) within the death domain domain at Thr(66), which is highly conserved among all IRAK family members. Mutation of Thr(66) to Ala impaired the autokinase activity of IRAK and reduced its association with iota PKC but not TRAM resulting in impaired NGF- as well as IL-1-induced NF-kappaB activation. These findings provide insight into the underlying mechanism whereby IRAK regulates the kappaB pathway and reveal that IRAK is a substrate of iota PKC.