Series Introduction: JAK-STAT signaling in human disease

JAK-STAT signaling in human diseaseCytokines, a large family of extracellular ligands, stimulate biological responses in virtually all cell types.One important subfamily of cytokines, the hematopoietins, evolved largely to regulate host responses to exogenous stresses, especially infection with pathogens.They stimulate these responses by binding to and activating a family of structurally and functionally conserved receptors.As is the case for many types of receptor families, downstream signaling entails tyrosine phosphorylation.However, the activation of the Janus kinases (Jaks) and their downstream signal transducer and activator of transcription (Stat) proteins is both characteristic of and unique to this hematopoietin family.This signaling paradigm first appeared in invertebrates and has continued to grow in complexity through vertebrate and mammalian evolution.There are about 50 members of the hematopoietin family in mammals, and they transduce their signals through four Jaks and seven Stats.Consistent with their identity as ILs, many of these ligands play a critical role in regulating leukocyte maturation and activity.Others regulate more central aspects of cellular homeostasis, reflecting the role Stats play in invertebrates.This Perspective series will provide an overview of the Jak-Stat pathway (reviewed in more detail in refs.1-4) and will explore the important role this pathway plays in regulating immune responses and cellular homeostasis in human health and disease.The series will explore human ailments affected by this pathway, including immunodeficiency, asthma, and cancer.It will also examine the role Stats play in regulating innate immunity and the unique role Stat3 plays in regulating cellular homeostasis.