**5.2 Cytokine receptors**

Cytokines such as hematopoietic growth factors and interleukins play essential roles in hematopoiesis. Cbl becomes tyrosine phosphorylated upon stimulation through various cytokine receptors (Table 2), and hematopoietic cells deficient in Cbl activity show enhanced sensitivity to cytokines (Rathinam et al., 2008; Sanada et al., 2009; Naramura et al., 2010). Receptors for these factors do not possess cytoplasmic tyrosine kinases but they activate the Janus kinase/Signal Transducers and Activators of Transcription (JAK/STAT) pathway (Yoshimura, 2009). Ligand binding induces receptor oligomerization, which activate associated JAK kinases and they, in turn, phosphorylate the receptor cytoplasmic domains and create binding sites for SH2-containing proteins.

There is no solid experimental evidence supporting the direct interaction between the JAK/STAT pathway and Cbl. Activation of the JAK/STAT pathway induces the expression of Suppressor of Cytokine Signaling (SOCS) family proteins, which function as E3 ubiquitin ligases for this pathway.

In addition to the JAK/STAT pathway, ligand binding to cytokine receptors activate the Ras-MAPK pathway through adaptor proteins such as APS and Grb2. Activation of this pathway is required for cell proliferation. As discussed above, these adaptor proteins are know to interact with Cbl, providing a potential link between the cytokine pathway and the Cbl family proteins.
