IL-7 signaling pathway (WP205)

Interleukin-7 (IL-7) was discovered in the year 1988 as a factor that enhanced the growth of murine B-cell precursors in bone marrow culture system. It was also known as lymphopoietin 1and pre-B cell factor. IL-7 plays an important role in the development of B and T cells in mouse and T cells in humans. It is also essential for mature and naive T-cell's survival and proliferation. Human IL-7 gene maps to chromosome 8 and is about 72kb in length. The protein encoded by this gene is 177 amino acids in length with a molecular weight of 20 kDa. The active form of IL-7 in humans is a glycoprotein of 25 kDa. In humans IL-7 has been shown to be produced from intestinal epithelial cells, keratinocytes , hepatic tissues, peripheral blood dendritic cells, follicular dendritic cells, endothelial cells, smooth muscle cells and fibroblasts. The IL-7 receptor consists of IL-7 receptor alpha chain (IL-7Rα) and a common gamma chain (γc). The gamma chain is also shared by IL-2, IL-4, IL-9, IL-15 and IL-21 receptors. The signaling pathways activated upon IL-7 binding to the receptor complex are JAK-STAT, PI-3 kinase and Src kinase pathways. JAK3, a protein tyrosine kinase is constitutively associated with the carboxy-terminal region of the gamma chain. Studies in mice lacking JAK3 have shown that it is required for transducing γc dependent signals. Mutations in JAK3 and γc have been shown to be associated with the autosomal recessive form of T-B + SCID. JAK1, another protein tyrosine kinase is associated with IL-7Rα chain and is activated upon IL-7 binding. JAK1 deficient mice shows severely impaired thymic development and no hematopoietic colony formation in response to IL-7. IL-7 would first bind to IL-7Rα and then associates with the gamma chain, bringing their intracellular domains bearing JAK1 and JAK3 together. JAK3 phosphorylates IL-7Rα chain creating docking sites for the transcription factors, STAT1, STAT3, and STAT5. JAK1 and JAK3 phosphorylate these STAT molecules and induces their dimerization and translocation to the nucleus where they activate specific target genes. PTK2B, a protein tyrosine kinase has been shown to be associated with JAK1 and plays an important role in the survival of thymocyte cell line. The enzymatic activity and its phosphorylation are highly induced by IL-7. PI-3 kinase pathway is also activated by IL-7 and this pathway is essential for the survival and proliferation of human T cell precursors. PI-3 kinase interacts with IL-7Rα upon IL-7 stimulation and activates its downstream target, AKT and its activation is mediated by γc. AKT in turn activates GSK3 beta and Bad, the death protein. Survival of pro T-cell survival by regulating Bad via PI3 kinase/AKT pathway is mediated by IL-7. IL-7 also mediates the downregulation of cyclin-dependent kinase inhibitor 1B through the PI-3 kinase pathway and this effect is required for cell proliferation. IL-7 also induces the phosphorylation of a Src kinase family member, Fyn which is constitutively associated with IL7RA. In addition, IL-7 induces phosphorylation of MAPK family members including MAPK1 and MAPK3. Please access this pathway at [http://www.netpath.org/netslim/IL_7_pathway.html NetSlim] database. If you use this pathway, please cite following paper: Kandasamy, K., Mohan, S. S., Raju, R., Keerthikumar, S., Kumar, G. S. S., Venugopal, A. K., Telikicherla, D., Navarro, J. D., Mathivanan, S., Pecquet, C., Gollapudi, S. K., Tattikota, S. G., Mohan, S., Padhukasahasram, H., Subbannayya, Y., Goel, R., Jacob, H. K. C., Zhong, J., Sekhar, R., Nanjappa, V., Balakrishnan, L., Subbaiah, R., Ramachandra, Y. L., Rahiman, B. A., Prasad, T. S. K., Lin, J., Houtman, J. C. D., Desiderio, S., Renauld, J., Constantinescu, S. N., Ohara, O., Hirano, T., Kubo, M., Singh, S., Khatri, P., Draghici, S., Bader, G. D., Sander, C., Leonard, W. J. and Pandey, A. (2010). NetPath: A public resource of curated signal transduction pathways. Genome Biology. 11:R3. Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP205 CPTAC Assay Portal]
last edited

Authors

A.Pandey, MaintBot, Khanspers, MartijnVanIersel, AlexanderPico, NetPath, Christine Chichester, Zari, Egonw, Mkutmon, L Dupuis, and Eweitz

Cited In

Organism

Homo sapiens

Communities

Annotations

Pathway Ontology: interleukin-7 signaling pathway Interleukin mediated signaling pathway

Participants

Label Type Compact Identifier
FYN Protein ncbigene:2534
MAP2K1 Protein ncbigene:5604
BCL2L1 Rna ncbigene:598
PTK2B Protein ncbigene:2185
CDKN1B Rna ncbigene:1027
STAT5A Protein ncbigene:6776
CCND1 Rna ncbigene:595
MAP2K2 Protein ncbigene:5605
MYC Rna ncbigene:4609
GSK3B Protein ncbigene:2932
STAT5B Protein ncbigene:6777
PIK3R2 Protein ncbigene:5296
IL2RG Protein ncbigene:3561
MAPK3 Protein ncbigene:5595
JAK1 Protein ncbigene:3716
IL7 Protein ncbigene:3574
STAT5A Protein ncbigene:6776
IL7R Protein ncbigene:3575
STAT3 Protein ncbigene:6774
BAD Protein ncbigene:572
MAPK1 Protein ncbigene:5594
AKT1 Protein ncbigene:207
JAK3 Protein ncbigene:3718
PIK3R1 Protein ncbigene:5295
IL2RA Rna ncbigene:3559
STAT5B Protein ncbigene:6777
STAT1 Protein ncbigene:6772

References

  1. Kandasamy K, Mohan SS, Raju R, Keerthikumar S, Kumar GSS, Venugopal AK, et al. NetPath: a public resource of curated signal transduction pathways. Genome Biol. 2010 Jan 12;11(1):R3. PubMed Europe PMC Scholia