PLATELET-DERIVED GROWTH-FACTOR INDUCES PHOSPHORYLATION OF MULTIPLE JAK FAMILY KINASES AND STAT PROTEINS

Receptors for interferons and other cytokines signal through the actio n of associated protein tyrosine kinases of the JAK family and latent cytoplasmic transcription factors of the STAT family, Genetic and bioc hemical analysis of interferon signaling indicates that activation of STATs by interferons requires two distinct JAK family kinases. Loss of either of the required JAKs prevents activation of the other JAK and extinguishes STAT activation. These observations suggest that JAKs pro vide interferon receptors with a critical catalytic signaling function and that at least two JAKs must be incorporated into an active recept or complex. JAK and STAT proteins are also activated by ligands such a s platelet-derived growth factor (PDGF), which act through receptors t hat possess intrinsic protein tyrosine kinase activity, raising questi ons about the role of JAKs in signal transduction by this class of rec eptors. Here, we show that all three of the ubiquitously expressed JAK s-JAK1, JAK2, and Tyk2-become phosphorylated on tyrosine in both mouse BALB/c 3T3 cells and human fibroblasts engineered to express the PDGF -beta receptor. All three proteins are also associated with the activa ted receptor. Through the use of cell lines each lacking an individual JAK, we find that in contrast to interferon signaling, PDGF-induced J AK phosphorylation and activation of STAT1 and STAT3 is independent of the presence of any other single JAK but does require receptor tyrosi ne kinase activity. These results suggest that the mechanism of JAK ac tivation and JAK function in signaling differs between receptor tyrosi ne kinases and interferon receptors.