The Proto-Oncogene Cot Kinase Participates in CD3/CD28 Induction of NF-κB Acting through the NF-κB-Inducing Kinase and IκB Kinases

Lin, Xin; Cunningham, Emmett T.; Mu, Yajun; Geleziunas, Romas; Greene, Warner C.

doi:10.1016/s1074-7613(00)80027-8

Cited by 201 publications

(195 citation statements)

References 57 publications

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“…Overexpression of TPL-2 also activates NFAT (nuclear factor of activated T cells) in Jurkat T cells and induces IL-2 (interleukin-2) production [22]. IL-2 induction by TPL-2 has also been suggested to involve activation of NF-κB transcription factors via the related MAP3 kinase NIK [23,24]. Transfection experiments in Jurkat T cells indicate that TPL-2 may control NF-κB activity by modulating the transactivation potential of the RelA transcription factor [25,26].…”

Section: S125mentioning

confidence: 99%

Regulation and function of TPL-2, an IκB kinase-regulated MAP kinase kinase kinase

Gantke¹,

Sriskantharajah²,

Ley³

2010

Cell Res

131

158

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The IκB kinase (IKK) complex plays a well-documented role in innate and adaptive immunity. This function has been widely attributed to its role as the central activator of the NF-κB family of transcription factors. However, another important consequence of IKK activation is the regulation of TPL-2, a MEK kinase that is required for activation of ERK-1/2 MAP kinases in myeloid cells following Toll-like receptor and TNF receptor stimulation. In unstimulated cells, TPL-2 is stoichiometrically complexed with the NF-κB inhibitory protein NF-κB1 p105, which blocks TPL-2 access to its substrate MEK, and the ubiquitin-binding protein ABIN-2 (A20-binding inhibitor of NF-κB 2), both of which are required to maintain TPL-2 protein stability. Following agonist stimulation, the IKK complex phosphorylates p105, triggering its K48-linked ubiquitination and degradation by the proteasome. This releases TPL-2 from p105-mediated inhibition, facilitating activation of MEK, in addition to modulating NF-κB activation by liberating associated Rel subunits for translocation into the nucleus. IKK-induced proteolysis of p105, therefore, can directly regulate both NF-κB and ERK MAP kinase activation via NF-κB1 p105. TPL-2 is critical for production of the proinflammatory cytokine TNF during inflammatory responses. Consequently, there has been considerable interest in the pharmaceutical industry to develop selective TPL-2 inhibitors as drugs for the treatment of TNF-dependent inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease. This review summarizes our current understanding of the regulation of TPL-2 signaling function, and also the complex positive and negative roles of TPL-2 in immune and inflammatory responses.

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Section: S125mentioning

confidence: 99%

Regulation and function of TPL-2, an IκB kinase-regulated MAP kinase kinase kinase

Gantke¹,

Sriskantharajah²,

Ley³

2010

Cell Res

131

158

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“…A likely answer is that these upstream kinases have unique substrates which do not belong to the MAPK modules. In fact, MEKK1 (Nakano et al, 1998), MEKK2 and3 (Zhao andLee, 1999), Tpl2 (Belich et al, 1999;Lin et al, 1999) and TAK1 (Ninomiya-Tsuji et al, 1999) can also activate NF-kB by phosphorylating certain components in this pathway. Alternatively, the divergence of upstream kinases may be utilized by cells to discriminate and di erentially respond to a wide variety of extracellular stimuli such as growth factors, cytokines and physicochemical stressors.…”

Section: Upstream Kinases In the Jnk And P38 Modulesmentioning

confidence: 99%

From receptors to stress-activated MAP kinases

1999

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The cell signaling pathways that culminate in activation of a family of stress-activated MAP kinases are beginning to be de®ned. Determination of cell life and cell death is known to largely depend on the balance of intrinsic life and death signals within cells. Recently, two representative mammalian stress-activated kinases, the JNK and p38 MAP kinases, have been implicated in determination of cell fate by modifying the life, death and di erentiation signals. However, the molecular mechanisms by which extracellular signals are transmitted from membrane receptors to the most upstream kinases in the JNK and p38 signaling modules are not fully understood. This review will provide an overview of current knowledge of molecular links between in¯amma-tory cyokine receptors and stress-activated MAP kinase cascades.

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“…Tpl-2 has also been implicated in the activation of nuclear factor-κB (NF-κB) [140,141]. NF-κB is a ubiquitous transcription factor that is involved in proliferation, apoptosis and the inflammatory response.…”

Section: Signal Diversification : Multi-protein Kinase Complexesmentioning

confidence: 99%

“…Ras and Raf can activate NF-κB quite efficiently, but, despite vigorous efforts, the mechanism has remained elusive. Suggestions include Tpl-2 increasing the level of active NF-κB by enhancing the proteolysis of p105, an NF-κB precursor molecule [141], or inducing the phosphorylation of IκB, marking it for destruction [140]. Rsk, an ERK-activated protein kinase, can also phosphorylate IκB on serine-32 [142].…”

Section: Signal Diversification : Multi-protein Kinase Complexesmentioning

confidence: 99%

Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions

Kölch

2000

Biochemical Journal

1,040

118

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The Ras\Raf\MEK (mitogen-activated protein kinase\ERK kinase)\ERK (extracellular-signal-regulated kinase) pathway is at the heart of signalling networks that govern proliferation, differentiation and cell survival. Although the basic regulatory steps have been elucidated, many features of this pathway are only beginning to emerge. This review focuses on the role of protein-protein interactions in the regulation of this pathway, INTRODUCTIONThe mitogen-activated protein kinase (MAPK) pathway is one of the primordial signalling systems that Nature has used in several permutations to accomplish an amazing variety of tasks. It exists in all eukaryotes, and controls such fundamental cellular processes as proliferation, differentiation, survival and apoptosis. The basic arrangement includes a G-protein working upstream of a core module consisting of three kinases : a MAPK kinase kinase (MAPKKK) that phosphorylates and activates a MAPK kinase (MAPKK), which in turn activates MAPK ( Figure 1). This set-up provides not only for signal amplification, but, maybe even more importantly, for additional regulatory interfaces that allow the kinetics, duration and amplitude of the activity to be precisely tuned. At present we can distinguish six MAPK modules, which share structurally related components, but seem to mediate specific biological responses. For recent reviews on MAPK pathways, the reader is referred to references [1][2][3]. Here we will focus on the regulation of the ERK (extracellular-signal-regulated kinase) pathway, which features Ras as G-protein, Raf as MAPKKK, MEK (MAPK\ERK kinase) as MAPKK and ERK as MAPK.Despite enjoying a decade in the limelight of scientific interest and revealing a plethora of new insights into the circuitry of signalling pathways in general, this pathway still holds many secrets. These pertain mainly to the regulation of Raf, and to a deeper understanding of how specific biological responses are encoded by spatial and temporal changes in the activity and subcellular distribution of the pathway components, and how these fluctuations are orchestrated at the molecular level. Work from many laboratories has highlighted protein-protein interactions as powerful means of co-ordinating signalling processes, most strikingly exemplified by the assembly of multi-protein signalling complexes on activated receptors, or of transcriptionfactor complexes on gene promoters. However, it is becoming Abbreviations used : Bcr, Breakpoint cluster region ; BXB, isolated Raf-1 kinase domain ; CNK, connector-enhancer of KSR ; CK2, casein kinase 2 ; CRD, cysteine-rich domain ; DEF, docking site for ERK, FxFP ; DLK, dual leucine-zipper-bearing kinase ; ERK, extracellular-signal-regulated kinase ; Hsp, heat-shock protein ; KIM, kinase interaction motif ; IκB, inhibitor of NF-κB ; JNK, c-Jun N-terminal kinase ; KSR, kinase suppressor of Ras ; MAPK, mitogen-activated protein kinase ; MAPKK, MAPK kinase ; MAPKKK, MAPK kinase kinase ; MEK, MAPK/ERK kinase ; MEKK, MEK kinase ; MP1, MEK partner 1 ; MUK, MAPK upstream kin...

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The Proto-Oncogene Cot Kinase Participates in CD3/CD28 Induction of NF-κB Acting through the NF-κB-Inducing Kinase and IκB Kinases

Cited by 201 publications

References 57 publications

Regulation and function of TPL-2, an IκB kinase-regulated MAP kinase kinase kinase

Regulation and function of TPL-2, an IκB kinase-regulated MAP kinase kinase kinase

From receptors to stress-activated MAP kinases

Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions

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