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Differential requirement for STAT by gain-of-function and wild-type receptor tyrosine kinase Torso in Drosophila
Willis X Li1, Herve Agaisse, Bernard Mathey-Prevot
1Department of Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA. willis_li@URMC.Rochester.edu
Abstract:
Malignant transformation frequently involves aberrant signaling from receptor tyrosine kinases (RTKs). These receptors commonly activate Ras/Raf/MEK/MAPK signaling but when overactivated can also induce the JAK/STAT pathway, originally identified as the signaling cascade downstream of cytokine receptors. Inappropriate activation of STAT has been found in many human cancers. However, the contribution of the JAK/STAT pathway in RTK signaling remains unclear. We have investigated the requirement of the JAK/STAT pathway for signaling by wild-type and mutant forms of the RTK Torso (Tor) using a genetic approach in Drosophila. Our results indicate that the JAK/STAT pathway plays little or no role in signaling by wild-type Tor. In contrast, we find that STAT, encoded by marelle (mrl; DStat92E), is essential for the gain-of-function mutant Tor (Tor(GOF)) to activate ectopic gene expression. Our findings indicate that the Ras/Raf/MEK/MAPK signaling pathway is sufficient to mediate the normal functions of wild-type RTK, whereas the effects of gain-of-function mutant RTK additionally require STAT activation.
Insights
Receptor tyrosine kinases (RTKs) can activate Ras/Raf/MEK/MAPK signaling. However, gain-of-function mutant RTKs also require the JAK/STAT pathway, involving STAT, for ectopic gene expression.
Area of Science:
- Cellular signaling pathways
- Molecular oncology
- Developmental biology
Background:
- Receptor tyrosine kinases (RTKs) are crucial in cell signaling and frequently dysregulated in cancer.
- While RTKs typically activate Ras/Raf/MEK/MAPK pathways, their overactivation can also engage the JAK/STAT pathway.
- The precise role of the JAK/STAT pathway in RTK signaling, particularly in oncogenesis, remains incompletely understood.
Purpose of the Study:
- To investigate the necessity of the JAK/STAT pathway for signaling mediated by wild-type and mutant forms of the Drosophila RTK Torso (Tor).
- To elucidate the distinct signaling requirements for normal versus aberrant RTK activation.
Main Methods:
- Utilized a genetic approach in Drosophila melanogaster.
- Examined the signaling output of wild-type Tor and a gain-of-function mutant (Tor(GOF)).
- Assessed the requirement for the JAK/STAT pathway component, STAT (encoded by marelle/mrl; DStat92E).
Main Results:
- Signaling by wild-type Tor minimally or not at all depends on the JAK/STAT pathway.
- STAT activation is essential for Tor(GOF) to induce ectopic gene expression.
- The Ras/Raf/MEK/MAPK pathway is sufficient for wild-type RTK functions.
Conclusions:
- Gain-of-function mutant RTK signaling exhibits distinct requirements compared to wild-type RTK signaling.
- Aberrant RTK activation, unlike normal signaling, necessitates STAT activation in addition to Ras/Raf/MEK/MAPK pathway activity.
- These findings highlight the context-dependent roles of signaling pathways in RTK-mediated cellular processes and cancer.