Negative Regulation of Haematopoiesis: Role of Inhibitory Adaptors

Cytokine signalling is initiated through ligand interaction with specific members of the cytokine receptor superfamily. The subsequent receptor oligomerization and conformational change result in activation of either an intrinsic kinase domain or receptor associated kinases, notably the Janus (JAK) family of cytoplasmic tyrosine kinases. The activated JAKs phosphorylate tyrosine residues in the receptor and subsequently downstream substrates, such as the signal transducers and activators of transcription (STAT) proteins. Once recruited to the receptor complex, STAT proteins are themselves phosphorylated on tyrosine, dimerize and translocate into the nucleus, where they activate the transcription of genes mediating cytokine-induced responses (Ortmann et al., 2000). Cytokines also activate other signaling cascades, such as the Ras/Mitogen-Activated Protein Kinase (MAPK) and the Phosphoinositide 3-kinase (PI3K)/Akt pathways. These cascades have been implicated in the proliferation, survival, and differentiation of several cell types in the haematopoietic system (Geest and Coffer, 2009; Leevers et al., 1999. However, all these signalling pathways require precise cellular control and their deregulation has been implicated in haematopoietic disorders, autoimmune and chronic inflammatory diseases and cancer, making it important to understand the mechanisms by which these cytokine-mediated signalling pathways are controlled (Schade et al., 2006; Khwaja, 2006).