The biological function of the proto-oncogene Cot/tpl-2 (MAP kinase kinase kinase 8)

Margarita Fernandez, Irene Soria, Marta Lopez Pelaez, Antonio Martin-Duce, Susana Alemany

    Research output: Chapter in Book/Report/Conference proceedingChapter (peer-reviewed)

    Abstract

    Cot, as well as its murine homologue tpl-2, was
    discovered in a COOH–terminal truncated form that unmasks the
    transformation capacity of the protein. The COOH-terminal
    domain of wt Cot contains an amino acid sequence that is a
    recognition signal for degradation via proteasome, besides, this
    domain of wt Cot is also an autoinhibitory domain of the specific
    activity of the wild type form. These data explain the
    transformation capacity of trunc-Cot/tpl-2, that when
    overexpressed is capable of activating several MAP kinases
    pathways as well as AP-1, NFAT, and NF-?B2 transcriptional
    activities. Earlier sobreexpression experiments lead to the proposal
    that Cot/tpl-2 could be involved in proliferative signalling, but the
    use of new technologies such as genetically modifies mice and
    interference RNA end up with the already accepted hypothesis that
    Cot/tpl-2 is involved in immune innate and adaptive processes.
    Cot/tpl-2 is activated in response to the activation of the TLR/IL-1
    receptor superfamily as well as in response to the activation of
    some receptors of the TNF family. Independently of the cell system
    it is accepted that in resting cells Cot/tpl-2 forms a stable and inactive complex with
    p105 NF-?B among other proteins to protect it from degradation, adequate TLR/IL-
    1R stimulation induces the activation of the IKK complex that targets p105 NF-?B
    to be rapidly degraded by the proteasome pathway to p50 NF-?B, a subunit of the
    NF-?B transcription factor. Consequently Cot/tpl-2 is released from the complex
    and susceptible to transduce the activatory signal, leading to the activation of the
    MEK1-Erk1/Erk2 pathway. However, actually it is not completely understood all
    the requests that Cot/tpl-2 needs to be fully active and to this end it is also accepted
    that Cot/tpl2 requires to be phosphorylated. In addition the possibility that the
    requirements vary from cell system to cell system cannot be excluded.
    Physiologically, Cot/tpl-2 is involved in provoking innate immunity to establish
    adaptive immunity. In fact it is the unique MAP3K that activates Erk1/Erk2 when
    the TLRs/IL-1 receptors are activated and mediates the production of pro-
    inflammatory cytokines, such as TNF?, IL-1, or IL-6. More recently it has been
    shown that Cot/tpl-2 has the capacity to regulate the balance between Th1 and Th2
    cytokines. All these data indicate that, although mutations in Cot gene result in the
    expression of a protein linked with cell malignancies, physiologically wt Cot/tpl-2
    is involved in innate and adaptive immunity.
    Original languageEnglish
    Title of host publicationEmerging Signaling Pathways in Tumor Biology
    EditorsPedro A. Lazo
    Place of PublicationKerala
    PublisherTransworld Research Network
    Pages25-41
    Number of pages17
    ISBN (Electronic)978-81-7895-477-6
    Publication statusPublished - 2010

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