Interleukin (IL) Pathway

Proteins of interleukins (IL) family regulate numerous biochemical events, for example, cellular proliferation and long-term survival. The major pathways involved in these events are the JAK kinases, signal transducers and activators of transcription (STATs), mitogen activated protein kinase (MAPK) and src-family kinases and phosphotidylinositol 3-kinase (PI 3K). These pathways are introduced in detail in the following sections.



JAKS is a family including 4 signal-transducing tyrosine kinases JAK1, JAK2, JAK3 and TYK2. Those proteins are associated with the intracellular domains of many cytokine receptors. JAK kinases are non-receptor protein tyrosine kinases, first identified in the Interferon system and later found to be associated with all Type I and Type II cytokine receptors, as well as other receptor types. IL proteins activate JAK1 and JAK3. JAK1 is ubiquitously expressed in lymphoid cells.



The MAPK pathway is connected to the IL 2R via the adaptor molecule Shc. Shc binds to a consensus sequence recognized by phospho-tyrosine-binding (PTB) domains. Shc recruits the adaptor molecule Grb2 and the nucleotide exchange 15 factor SOS. This engages the Ras-Raf-MAPK pathway that eventually upregulates various genes such as c-fos and bcl-2.



The molecular strategies used by cytokines to prevent apoptosis are incompletely understood, but the PI 3K pathway has been strongly implicated. PI 3K is a lipid kinase that catalyzes phosphorylation of phosphotidyl inositol (PI), generating the intracellular messengers, PI 3, PI 3,4-bisphosphate, and PI 3,4,5-triphosphate. The PI 3K family members are composed of a catalytic subunit (p110α, β, δ) independently paired with a regulatory subunit (p85α, p85β, p55, p50, and p101). PI 3K can be activated by direct association with phosphorylated tyrosine residues bearing the YXXM motif on the cytoplasmic tail of cytokine receptors. Alternatively, PI 3K can be recruited to the receptor complex through adaptor molecules such as Shc, Gab2 and Grb2.


SRC-Family and Syk Kinases

SRC and Syk kinases are non-receptor protein tyrosine kinases (PTK) such as Lck and that frequently associate with the plasma membrane. These kinases contain SH2 and SH3 domains that interact with phosphorylated tyrosine residues and proline rich regions, respectively. In vitro experiments have shown that both Lck and Syk are phosphorylated in response to IL 2. The physiological roles of Lck and Syk remain unclear. Lck is expressed primarily in T and NK cells and is critical for TCR signals, while Syk is known to play an import role in Fc receptor and B cell antigen receptor (BCR) signaling. However, T cells from Lck-/- mice still proliferate in response to IL 2, as do Lck-/- CTLL-2 lines. Similarly, Syk–deficient mice appear to exhibit a normal response to IL 2.



STATs proteins are transcription factors present in a latent form in the cytoplasm, including seven structurally related proteins STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6. STATs are rapidly activated through tyrosine phosphorylation by JAK kinases. Activation of STAT proteins is initiated by their recruitment to phosphorylated tyrosine residues on the cytokine receptor chain. Binding occurs via SH2 domains on the STATs. Upon recruitment, STATs are phosphorylated, presumably by one or both of the JAK kinases. The activated STAT proteins translocate to the nucleus to activate target gene expression.



Interleukin (IL) signaling pathway related literatures

1. Weaver C T, Hatton R D, Mangan P R, et al. IL-17 family cytokines and the expanding diversity of effector T cell lineages[J]. Annu. Rev. Immunol., 2007, 25: 821-852.

2. Seger R, Krebs E G. The MAPK signaling cascade[J]. The FASEB journal, 1995, 9(9): 726-735.

3. Lowell C A. Src-family and Syk kinases in activating and inhibitory pathways in innate immune cells: signaling cross talk[J]. Cold Spring Harbor perspectives in biology, 2011, 3(3): a002352.


IL12 receptors