Figure 5

Crosstalk of the canonical NF-κB pathway with other signaling processes. (A) Many different kinases can phosphorylate and activate the IKKα and IKKβ subunits of the IKK complex or can enhance NF-κB transcriptional activity. Important examples are glycogen synthase kinase 3β (GSK3β), Protein Kinase B (PKB or Akt), Protein Kinase R (PKR), Protein Kinase C (PKC), Mitogen-Activated Type 3-Protein Kinase 7 (MAP3K7 or TAK1), p38 MAP Kinases or c-Jun N-terminal kinases (JNKs). (B) Various transcription factors such as p53, Ets Related Gene (ERG) or Signal Transducer and Activator of Transcription 3 (STAT3) can influence the transcriptional activity of NF-κB or directly activate transcription of NF-κB target genes. (C) microRNAs (miRNAs) can be target genes of the NF-κB signaling pathways or can affect the expression of NF-κB family members or effector molecules of the NF-κB activation pathway. (D) Prominent target genes of the NF-κB signaling pathway include anti-apoptotic genes as the Baculoviral IAP repeat-containing proteins (BIRCs or cIAPs) and the B-cell lymphoma 2 gene (Bcl-2), cytokines such as Interleukin-1 (IL-1), IL-6, IL-8 and chemokine (C-C motif) ligand 2 (CCL2), adhesion factors including the Vascular Cell Adhesion Molecule 1 (VCAM-1) and the Intercellular Cell Adhesion Molecule 1 (ICAM-1). (E) Another layer of complexity of NF-κB signaling are positive and negative feedback mechanism. Examples for positive feedback molecules are the X-linked inhibitor of apoptosis protein (XIAP) as well as TNFα or IL-1. Important negative feedback circuits are generated by the NF-κB target genes IκBα, Cylindromatosis (CYLD) or A20.