Activation of the IκB Kinases by RIP via IKKγ/NEMO-mediated Oligomerization

Poyet, Jean-Luc; Srinivasula, Srinivasa M.; Lin, Jun-Hsiang; Fernandes-Alnemri, Teresa; Shoji, Yasuhiro; Tsichlis, Philip N.; Alnemri, Emad S.

doi:10.1074/jbc.m006643200

Cited by 165 publications

(167 citation statements)

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“…This suggests that ANXA1 overexpression may enforce NEMO and RIP oligomerization, resulting in activation of IKK complex. This is in agreement with previous studies showing that enforced oligomerization of RIP, NEMO, IKKa, IKKb is sufficient for inducing IKK activation (Poyet et al, 2000). In addition, TRADD was found in smaller molecular weight fractions, while TAK1 was found in higher fractions in MCF7-V5 cells.…”

Section: Resultssupporting

confidence: 93%

Annexin-1 interacts with NEMO and RIP1 to constitutively activate IKK complex and NF-κB: implication in breast cancer metastasis

et al. 2011

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The molecular mechanisms underlying constitutive nuclear factor-jB (NF-jB) activation in solid tumors has not been elucidated. We show that Annexin-1 (ANXA1) is involved in this process, and suppression of ANXA1 in highly metastatic breast cancer cells impedes migration and metastasis capabilities in vitro and in vivo. ANXA1 expression correlates with NF-jB activity, suggesting that ANXA1 may be required for the constitutive activity of IjB kinase (IKK) and NF-jB in highly metatstatic breast cancer. Gel-filtration analysis demonstrated that ANXA1 co-elutes with the members of the IKK complex and NF-jB signaling pathway, and immunoprecipitation confirmed that ANXA1 can bind to and interact with IKKc or NEMO, but not IKKa or IKKb. Importantly, silencing of ANXA1 prevents the interaction of NEMO and RIP1, which indicates that ANXA1 is required for the recruitment of RIP1 to the IKK complex, which may be important for the activation of NF-jB. Downstream targets of NF-jB include uPA and CXCR4, which can be modulated by ANXA1 silencing. CXCR4-mediated migration of breast cancer cell lines in response to CXCL12 was significantly modulated by ANXA1, indicating its importance in the tissue-specific migration of breast cancer cells. Chromatin immunoprecipitation experiments confirmed that in ANXA1 overexpressed cells, NF-jB was recruited to CXCR4 promoter without external stimulation, indicating that ANXA1 is critical for the constitutive activation of NF-jB in breast cancer to promote metastasis. Finally, we show that ANXA1 overexpression enhances metastasis and reduces survival in an intracardiac metastasis model, while ANXA1-deficient mice crossed with MMTV-PyMT mice display significantly less metastasis than their heterozygous littermates, indicating that ANXA1 is an important gene in breast cancer metastasis. Our data reveal that ANXA1 can constitutively activate NF-jB in breast cancer cells through the interaction with the IKK complex, and suggests that modulating ANXA1 levels has therapeutic potential to suppress breast cancer metastasis.

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Section: Resultssupporting

confidence: 93%

Annexin-1 interacts with NEMO and RIP1 to constitutively activate IKK complex and NF-κB: implication in breast cancer metastasis

et al. 2011

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“…Oligomerization of IKK␥ is emerging as an important role in the activation of the IKK complex. Forced oligomerization of IKK␥ by fusion with the FKBP12 polypeptide leads to NF-B activation and the redistribution of the IKK subunits from uniform to punctate cytoplasmic staining (32). Tax also promotes the oligomerization of IKK␥ through a direct interaction (33).…”

Section: Discussionmentioning

confidence: 99%

Activation of NF-κB by the Human T Cell Leukemia Virus Type I Tax Oncoprotein Is Associated with Ubiquitin-dependent Relocalization of IκB Kinase

Harhaj

Sun

Harhaj

2007

Journal of Biological Chemistry

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Human T cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T cell leukemia. HTLV-1 encodes a trans-activating protein, Tax, which is largely responsible for the oncogenic properties of the virus. Tax promotes T cell transformation by deregulating the activity of various cellular factors, including the transcription factor NF-B. Tax activates the I B kinase (IKK) via physical interaction with the regulatory subunit, IKK␥, although it is unknown precisely how Tax activates the IKK complex. Here we show that Tax modulates the cellular localization of the IKK complex. The IKKs relocalize from a broad distribution in the cytoplasm to concentrated perinuclear "hot spots" in both HTLV-1-transformed lines and in Tax-expressing Jurkat cells. Relocalization of IKK is not observed with Tax mutants unable to activate NF-B, suggesting that only activated forms of IKK are relocalized. However, relocalization of IKK is strictly dependent on Tax expression because it does not occur in ATL cell lines that lack Tax expression or in Jurkat cells treated with phorbol 12-myristate 13-acetate and ionomycin. Furthermore, IKK␥ is required for redistribution because cells lacking IKK␥ were unable to relocalize IKK␣ upon expression of Tax. We also find that Tax ubiquitination likely regulates IKK relocalization because mutation of three critical lysine residues in Tax renders it unable to relocalize IKK and activate the canonical and noncanonical NF-B pathways. Finally, we have observed that the perinuclear IKK in Tax-expressing cells colocalizes with the Golgi, and disruption of Golgi with either nocodazole or brefeldin A leads to a redistribution of IKK to the cytoplasm. Together, these results demonstrate that Tax induces relocalization of the IKK complex in a ubiquitin-dependent manner, and dynamic changes in the subcellular localization of the IKK complex may be critical for Tax function.The human T cell leukemia virus type I (HTLV-1) 3 is associated with adult T cell leukemia (ATL), an aggressive malignancy of CD4 ϩ T cells, and a neuroinflammatory disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis (1). The HTLV-1 genome encodes a regulatory protein Tax in the pX region that plays a central role in HTLV-1-associated disease (2). Tax acts as a trans-activating protein that is critical for the expression of viral genes and also deregulates the expression of cellular genes. Tax regulates the expression of cellular genes by modulating signaling pathways such as NF-B, AP-1, CREB, and nuclear factor of activated T cells (3). Tax activation of NF-B is required for immortalization of T lymphocytes (4). Further, pharmacologic inhibition of NF-B leads to apoptosis of HTLV-1 transformed T cell lines and ATL cells (5).NF-B represents a family of transcription factors that regulate a wide variety of genes controlling cell survival, development, differentiation, and activation. NF-B family members include RelA (p65), c-Rel, RelB, p50, and p52, all of which contain a 300-amino acid Rel homology domain th...

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“…In the case of the TNF receptor I, associated proteins recruit the E2/E3 ligase complex consisting of UbcH5 and cIAP1, which subsequently forms ubiquitin chains of various linkages to RIP1 [11,12]. The TAB/TAK1 and IKK complexes are able to bind these ubiquitin chains, allowing the activated TAK1 to phosphorylate and activate IKK2 [13]. Additionally, oligomerization of the NEMO-IKK2 complex upon mixed ubiquitin chain binding can allow for TAK1-independent trans-autophosphorylation and activation of the IKK2 complex [12].…”

Section: The Canonical Pathwaymentioning

confidence: 99%

A single NFκB system for both canonical and non-canonical signaling

et al. 2010

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Two distinct nuclear factor κB (NFκB) signaling pathways have been described; the canonical pathway that mediates inflammatory responses, and the non-canonical pathway that is involved in immune cell differentiation and maturation and secondary lymphoid organogenesis. The former is dependent on the IκB kinase adaptor molecule NEMO, the latter is independent of it. Here, we review the molecular mechanisms of regulation in each signaling axis and attempt to relate the apparent regulatory logic to the physiological function. Further, we review the recent evidence for extensive cross-regulation between these two signaling axes and summarize them in a wiring diagram. These observations suggest that NEMO-dependent and -independent signaling should be viewed within the context of a single NFκB signaling system, which mediates signaling from both inflammatory and organogenic stimuli in an integrated manner. As in other regulatory biological systems, a systems approach including mathematical models that include quantitative and kinetic information will be necessary to characterize the network properties that mediate physiological function, and that may break down to cause or contribute to pathology.

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Activation of the IκB Kinases by RIP via IKKγ/NEMO-mediated Oligomerization

Cited by 165 publications

References 54 publications

Annexin-1 interacts with NEMO and RIP1 to constitutively activate IKK complex and NF-κB: implication in breast cancer metastasis

Annexin-1 interacts with NEMO and RIP1 to constitutively activate IKK complex and NF-κB: implication in breast cancer metastasis

Activation of NF-κB by the Human T Cell Leukemia Virus Type I Tax Oncoprotein Is Associated with Ubiquitin-dependent Relocalization of IκB Kinase

A single NFκB system for both canonical and non-canonical signaling

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