Structural Studies of Protein Tyrosine Kinases

Many important cellular signaling cascades are initiated at the cell surface by the binding of a polypeptide ligand to a transmembrane receptor possessing intrinsic tyrosine kinase activity in its cytoplasmic domain. The receptor tyrosine kinase (RTK) family includes, among others, the insulin receptor, insulin-like growth factor-1 (IGF1) receptor, epidermal growth factor receptor, fibroblast growth factor receptor and MuSK, the receptor for agrin. Ligand binding induces receptor oligomerization (growth factor receptors) or a conformational change within the receptor (insulin/IGF1 receptor), leading to autophosphorylation of specific tyrosine residues in the cytoplasmic domains of the receptors. Tyrosine autophosphorylation stimulates receptor catalytic activity and generates recruitment sites for downstream signaling proteins. RTKs are critical components in signal transduction pathways that mediate cell proliferation, differentiation, migration and metabolism, and are active during organismal development and adult homeostasis. RTKs also play primary roles in the onset or progression of pathological conditions such as diabetic retinopathy, atherosclerosis and cancer.

The Janus kinase (JAK) family comprises four non-receptor tyrosine kinases: JAK1-3 and TYK2. These proteins signal through the JAK-STAT (signal transducer and activator of transcription) pathway following cytokine stimulation, and are important for myeloid cell development, proliferation and survival and innate and adaptive immune responses. Mutations in JAKs, particularly in JAK2, which result in constitutive activation of JAKs, are causative for myeloproliferative neoplasms (MPNs).