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Updated: Jul 13, 2025
Dual Somatic Recordings from Gonadotropin-Releasing Hormone GnRH Neurons Identified by Green Fluorescent Protein GFP in Hypothalamic Slices
Published on: February 23, 2010
AXL receptor tyrosine kinase modulates gonadotropin-releasing hormone receptor signaling
Pardis Mohammadzadeh1, Mina Roueinfar1, Gregory C Amberg2
1Department of Biomedical Sciences, Colorado State University, 1617 Campus Delivery, Fort Collins, CO, 80523, USA.
Background:
Gonadotropin-releasing hormone (GnRH) receptors are essential for reproduction and are expressed in numerous urogenital, reproductive, and non-reproductive cancers. In addition to canonical G protein-coupled receptor signaling, GnRH receptors functionally interact with several receptor tyrosine kinases. AXL is a receptor tyrosine kinase expressed in numerous tissues as well as multiple tumors. Here we tested the hypothesis that AXL, along with its endogenous ligand Gas6, impacts GnRH receptor signaling.
Methods:
We used clonal murine pituitary αT3-1 and LβT2 gonadotrope cell lines to examine the effect of AXL activation on GnRH receptor-dependent signaling outcomes. ELISA and immunofluorescence were used to observe AXL and GnRH receptor expression in αT3-1 and LβT2 cells, as well as in murine and human pituitary sections. We also used ELISA to measure changes in ERK phosphorylation, pro-MMP9 production, and release of LHβ. Digital droplet PCR was used to measure the abundance of Egr-1 transcripts. A transwell migration assay was used to measure αT3-1 and LβT2 migration responses to GnRH and AXL.
Results:
We observed AXL, along with the GnRH receptor, expression in αT3-1 and LβT2 gonadotrope cell lines, as well as in murine and human pituitary sections. Consistent with a potentiating role of AXL, Gas6 enhanced GnRH-dependent ERK phosphorylation in αT3-1 and LβT2 cells. Further, and consistent with enhanced post-transcriptional GnRH receptor responses, we found that Gas6 increased the abundance of Egr-1 transcripts. Suggesting functional significance, in LβT2 cells, Gas6/AXL signaling stimulated LHβ production and enhanced GnRH receptor-dependent generation of pro-MMP9 protein and promoted cell migration.
Conclusions:
Altogether, these data describe a novel role for AXL as a modulator of GnRH receptor signaling. Video Abstract.
Insights
The receptor tyrosine kinase AXL, with its ligand Gas6, modulates gonadotropin-releasing hormone (GnRH) receptor signaling. This interaction enhances GnRH receptor responses, impacting cell signaling and migration.
Area of Science:
- Endocrinology and reproductive biology
- Molecular and cellular signaling
- Cancer biology
Background:
- Gonadotropin-releasing hormone (GnRH) receptors are crucial for reproduction and implicated in various cancers.
- GnRH receptors interact with receptor tyrosine kinases (RTKs), including AXL, which is prevalent in tumors.
- This study investigates the impact of AXL and its ligand Gas6 on GnRH receptor signaling.
Discussion:
- AXL and GnRH receptors are co-expressed in gonadotrope cell lines and pituitary tissues.
- Gas6, acting through AXL, potentiates GnRH-dependent ERK phosphorylation and Egr-1 transcript abundance.
- AXL signaling enhances GnRH receptor-mediated LHβ production, pro-MMP9 generation, and cell migration.
Key Insights:
- AXL acts as a novel modulator of GnRH receptor signaling pathways.
- The Gas6/AXL axis influences key downstream signaling events initiated by GnRH receptors.
- This interaction has functional implications for cell signaling, protein production, and cell motility.
Outlook:
- Further research into AXL's role in GnRH receptor-driven pathologies, particularly cancers.
- Exploring therapeutic strategies targeting the AXL-GnRH receptor interaction.
- Investigating the broader implications of RTK-GPCR crosstalk in endocrine regulation and disease.
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