Disease relevance of NLK

• Our previous study showed that NLK overexpression induces apoptosis in DLD-1 human colon cancer cells and that apoptosis induction presumably requires a mechanism other than the suppression of beta-catenin-TCF complex [1].
• A correlation between cytolysis of lymphocytes against a natural killer-resistant melanoma cell line (LAK-like activity) was found, but the role of LAK cells in vivo remains uncertain [2].
• We have investigated the susceptibility of human foreskin fibroblast (HFF) monolayers infected at low level with human cytomegalovirus (HCMV) strain AD 169, or a clinical HCMV isolate, to lysis mediated by interleukin-2(IL-2)-activated killer cells (LAK) [3].
• 4. Endothelium infected with herpes simplex virus for very brief periods (4 hr) becomes even more vulnerable to LAK cell-mediated injury [4].

High impact information on NLK

• Because NLK was recently shown to interact with STAT3, we explored the role of STAT3 in activating this pathway [5].
• STAT3 regulates Nemo-like kinase by mediating its interaction with IL-6-stimulated TGFbeta-activated kinase 1 for STAT3 Ser-727 phosphorylation [5].
• NLK function was found to be redundant with that of the MAP kinase ERK during mesoderm formation and to require the activity of the activating kinase TAK1 [6].
• From this screen, we isolated a novel RING finger protein that we term NARF (NLK associated RING finger protein) [7].
• NLK phosphorylated A-Myb, but did not induce A-Myb degradation [8].

Biological context of NLK

• Second, a loss of multiple NLK phosphorylation sites by truncation of the C-terminal region of c-Myb increases its stability [9].
• Furthermore, NLK induced the methylation of histone H3 at lysine-9 at A-Myb-bound promoter regions [8].
• Luciferase reporter gene assay with pNF-kappaB-Luc revealed that NLK could suppress transcription activity of NF-kappaB in a kinase-dependent manner [1].
• Our results suggest that NLK may suppress a wide range of gene expression, possibly through CBP [1].
• The induction of wild-type NLK in DLD-1 cells caused suppression of cell growth whereas the kinase-negative mutant did not [10].

Anatomical context of NLK

• We demonstrate that overnight exposure of LGL to as little as 1 nM okadaic acid induced an increase in natural killing against the K562 cell line, but does not induce LAK activity [11].
• Soluble HLA class I molecules in malignant pleural and peritoneal effusions and its possible role on NK and LAK cytotoxicity [12].
• The study has been performed on monocyte-depleted peripheral blood MNCs by using, the K-562 cell line as a target for NK activity and the HL-60 cell line for as a target LAK activity [13].

Regulatory relationships of NLK

• Furthermore, the expression of the STAT3(534-770) region in the nuclei of STAT3-knockdown cells enhanced the IL-6-induced NLK activation in a dose-dependent manner but not the TGFbeta-induced NLK activation [5].

Other interactions of NLK

• However, it appeared that transcription co-activators of NF-kappaB, such as CREB binding protein (CBP)/p300, were likely to be the direct targets of NLK, rather than NF-kappaB itself [1].
• Depletion of STAT3 diminished the IL-6-induced NLK activation by >80% without inhibiting IL-6-induced TAK1 activation or its nuclear entry [5].
• Our results suggest that overexpression of NLK may have targets other than TCF for induction of apoptosis in human colon carcinoma cells [10].

Analytical, diagnostic and therapeutic context of NLK

• Flow cytometry indicated that NLK expression increased the number of apoptotic cells but did not induce obvious cell cycle arrest [10].
• Apoptosis induction by wild-type NLK was confirmed using TUNEL assays [10].

References