Browsing Pathways

The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signalling pathway is a pathway with many functions, one of which is an anti-viral response. IFN-γ activates interferon gamma receptors 1 and 2 (INFGR1 and INFGR2), which are associated with Janus kinase 1 (JAK1) and Janus kinase 2 (JAK2) which leads to the phosphorylation of signal transducer and activator of transcription 1 (STAT1) homodimers. Phosphorylated STAT1 homodimers are translocated to the nucleus where it activates the transcription of gamma activated sequence (GAS) elements, which activates an inflammatory response and immunoregulation. INFGR1 and INFGR2 also phosphoylate STAT3 homodimers which are subsequently translocated to the nucleus where they also activate GAS elements. Type 1 interferons (IFNs) activate interferon alpha receptors 1 and 2 (IFNAR1 and IFNAR2) which are associated with tyrosine kinase 2 (TYK2) and JAK1 respectively. This receptor complex also phosphorylates STAT3 homodimers. The IFNAR complex phorphoylates STAT5 which binds with Crk-like protein (CRKL). This complex also activates the GAS elements in the nucleus. The main pathway of IFNAR1 and IFNAR2 is through the phosphorylation of STAT1 and STAT2. Together with interferon regulatory factor (IRF9) they form the interferon-stimulated gene factor 3 (ISGF3). The ISGF3 translocates to the nucleus and initiates the trascription of Interferon-sensitive response element (ISRE). This leads to an antiviral response, immunoregulation, antigen presentation, and checkpoint proteins. THE ISRE genes also activate IFN regulated genes. These along with lipopolysaccharides or foreign pathogens activates interferon Regulatory Factor 7 (IRF7). IRF7 is phosphorylated and bound with nuclear factor kappa B (NFKB). This causes the induction of type 1 INFs, which further activates the pathway. IFNAR1 and IFNAR2, activated by type 1 IFNs, signal through TYK2 and JAK1 to also trigger the activation of the NFKB pathway through phosphorylated STAT3, phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and TNF receptor-associated factors (TRAFs). They act through IKKa and IKKb to drive NFKB induction of genes associated with survival signals, antigen processing and presentation, and proliferation. Cytokines, like the various interleukins, activate their corresponding cytokine receptors/JAK complexes. This results in the phosphorylation of STATs, such as STAT3 and STAT5 or a STAT3 homodimer. These phosphorylated STATs are translocated to the nucleus where they transcribe genes involved in inflammation, angiogenesis, proliferation, and survival.

The branched chain amino acid (BCAA) leucine is able to signal transduction pathways that modulate translation initiation for protein synthesis in skeleton muscles. In the presence of leucine, hyperphosphorylation of 4E-BP1 causes its affinity for eIF4E to be lowered. This allows eIF4F protein complexes to recognize, unfold and guide the mRNA to the 43S preinitiation complex thereby increasing translation initiation. In addition, leucine has a transient affect on the release of insulin and/or enhances sensitivity of muscle cells to insulin. A culmination of both signals at the mammalian target of rapamycin (mTOR) and perhaps other signaling, such as PKCδ, are needed for maximum translation initiation to occur.

An interesting link has emerged between NAD+ metabolism, SIRT1, SIRT3, and mitochondrial function. NR and PARP inhibitors increased life span in worms via activation of the mitochondrial unfolded protein response UPRmt by sir2.1. Short-term (1 week) supplementation of these mice with NMN restored mitochondrial homeostasis in muscles, which suggests that NAD+ supplementation can restore some reversible aspects of the aging process. Both observations are consistent with the model indicating that an imbalance in the relative stoichiometries of mitochondria- versus nucleus-encoded ETC proteins may induce life-span extension via activation of the UPRmt. In support of such a mechanism, mutation or reduced function in nuclear genes encoding ETC components in yeast, Caenorhabditis elegans, Drosophila, and mice increase life span through activation of the mitochondrial unfolded protein response UPRmt. NAD salvage pathway is deficient in aging since the supplementation with NMN corrects defects associated with aging.

NAD+-dependent signalling pathways regulate many fundamental processes such as DNA repair, DNA transcription, cell proliferation, cell survival, cell cycle progression, apoptosis, and metabolism. These pathways are all linked to cancer development. Degradation of NAD will activate various biosynthetic pathways, which are crucial for incessant cancer cell proliferation.