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.
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 language | English |
|---|---|
| Title of host publication | Emerging Signaling Pathways in Tumor Biology |
| Editors | Pedro A. Lazo |
| Place of Publication | Kerala |
| Publisher | Transworld Research Network |
| Pages | 25-41 |
| Number of pages | 17 |
| ISBN (Electronic) | 978-81-7895-477-6 |
| Publication status | Published - 2010 |