Ihle: The biochemical basis by which various cytokines bring about their biological responses

A large number of physiological functions are regulated by cytokines that mediate their affects through interaction with members of the cytokine receptor superfamily. This family of receptors characteristically associates with members of the Janus tyrosine kinases (Jaks) which are activated following ligand binding. When activated, the Jaks phosphorylate the receptors and substrates that are recruited to the receptor complex through interactions with specific sites of tyrosine phosphorylation. This laboratory has a long-standing interest in the mechanisms by which cytokines mediate their affects. Our recent studies focus on defining the spectrum of cytokines that require each of the Jaks through gene knockouts and determining the mechanisms by which the Jaks are positively and negatively regulated. Once activated, cytokine receptors, such as the erythropoietin (Epo) receptor, activate many signaling pathways including the activation of proteins of the signal transducers and activators of transcription (Stats). A second major focus in the laboratory is to assess the role of these pathways in the function of individual cytokines. Studies have utilized gene disruption approaches to assess the roles of Stat4, Stat5a, Stat5b and Stat6 and have demonstrated that each of these Stats functions to mediate the responses of specific cytokines. Ongoing experiments are utilizing similar approaches to define the roles of other gene products which are transcriptionally activated or biochemically modified in response to cytokines. An additional approach has been to derive mutant mice in which receptors are mutated in such a manner as to eliminate their ability to activate specific pathways. Together the studies seek to provide the biochemical basis by which various cytokines bring about their biological responses.


Last update: April 2003