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Platelet-derived growth factor induces phosphorylation of multiple JAK family kinases and STAT proteins
M L Vignais1, H B Sadowski, D Watling
1Cold Spring Harbor Laboratory, New York 11724, USA.
Abstract:
Receptors for interferons and other cytokines signal through the action of associated protein tyrosine kinases of the JAK family and latent cytoplasmic transcription factors of the STAT family. Genetic and biochemical 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 provide interferon receptors with a critical catalytic signaling function and that at least two JAKs must be incorporated into an active receptor complex. JAK and STAT proteins are also activated by ligands such as platelet-derived growth factor (PDGF), which act through receptors that possess intrinsic protein tyrosine kinase activity, raising questions about the role of JAKs in signal transduction by this class of receptors. Here, we show that all three of the ubiquitously expressed JAKs--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 activated receptor. Through the use of cell lines each lacking an individual JAK, we find that in contrast to interferon signaling, PDGF-induced JAK phosphorylation and activation of STAT1 and STAT3 is independent of the presence of any other single JAK but does require receptor tyrosine kinase activity. These results suggests that the mechanism of JAK activation and JAK function in signaling differs between receptor tyrosine kinases and interferon receptors.
Insights
Interferon and PDGF signaling utilize Janus kinases (JAKs) and signal transducers of activation of transcription (STATs). However, PDGF-induced JAK activation differs from interferon signaling, highlighting distinct receptor tyrosine kinase mechanisms.
Area of Science:
- Molecular Biology
- Cell Signaling
- Immunology
Background:
- Cytokine receptors, including interferon receptors, signal via Janus kinases (JAKs) and signal transducers of activation of transcription (STATs).
- Interferon signaling requires at least two specific JAKs for STAT activation, suggesting a critical catalytic role for JAKs in this pathway.
- Platelet-derived growth factor (PDGF) also activates JAK and STAT proteins through receptors with intrinsic tyrosine kinase activity, raising questions about JAK involvement.
Purpose of the Study:
- To investigate the role and activation mechanisms of JAKs in PDGF receptor signaling.
- To compare JAK activation and function in response to interferon versus PDGF receptor stimulation.
- To determine the requirement of specific JAKs for PDGF-induced JAK and STAT activation.
Main Methods:
- Utilized mouse BALB/c 3T3 cells and human fibroblasts engineered to express the PDGF-beta receptor.
- Examined tyrosine phosphorylation of JAK1, JAK2, and Tyk2 in response to PDGF stimulation.
- Employed cell lines deficient in individual JAKs to assess the necessity of each JAK for PDGF signaling.
Main Results:
- All three ubiquitously expressed JAKs (JAK1, JAK2, Tyk2) were phosphorylated on tyrosine and associated with the activated PDGF-beta receptor.
- PDGF-induced JAK phosphorylation and subsequent STAT1 and STAT3 activation were independent of any single JAK's presence.
- PDGF-induced JAK activation critically required intrinsic receptor tyrosine kinase activity, unlike interferon signaling.
Conclusions:
- The mechanism of JAK activation and function differs significantly between interferon receptors and receptor tyrosine kinases like the PDGF receptor.
- PDGF receptor signaling involves a distinct JAK activation cascade compared to cytokine receptor signaling.
- These findings elucidate differential roles of JAKs in diverse signal transduction pathways.