AXL/Gas6 signaling mechanisms in the hypothalamic-pituitary-gonadal axis

Abstract

AXL is a receptor tyrosine kinase commonly associated with a variety of human cancers. Along with its ligand Gas6 (growth arrest-specific protein 6), AXL is emerging as an important regulator of neuroendocrine development and function. AXL signaling in response to Gas6 binding impacts neuroendocrine structure and function at the level of the brain, pituitary, and gonads. During development, AXL has been identified as an upstream inhibitor of gonadotropin receptor hormone (GnRH) production and also plays a key role in the migration of GnRH neurons from the olfactory placode to the forebrain. AXL is implicated in reproductive diseases including some forms of idiopathic hypogonadotropic hypogonadism and evidence suggests that AXL is required for normal spermatogenesis. Here, we highlight research describing AXL/Gas6 signaling mechanisms with a focus on the molecular pathways related to neuroendocrine function in health and disease. In doing so, we aim to present a concise account of known AXL/Gas6 signaling mechanisms to identify current knowledge gaps and inspire future research.

AXL receptor tyrosine kinase modulates gonadotropin-releasing hormone receptor signaling

“…However, our observations are not without incongruities, such as the temporal discord between changes in ERK signaling and Egr-1 transcription and disparities between in αT3-1 and LβT2 cells. We suggest that these apparent disconnects arise not only from the many differences between αT3-1 and LβT2 cells [ 29 , 30 ], but also the intrinsic complexities of AXL and GnRH receptor signaling mechanisms [ 16 ]. Additionally, the less-than-optimal efficacy and tolerability of current medications manipulating GnRH receptor expressing cells (e.g., gonadotropes) supports the need for novel pharmacotherapeutic targets.…”

“…Following activation, intrinsic AXL tyrosine kinase activity phosphorylates C-terminal tyrosine residues which leads to recruitment and activation of multiple intracellular signaling proteins [ 12 – 16 ]. Examples include phosphatidylinositol 3-kinase (PI3K), Src tyrosine kinase, phospholipase C-γ, protein kinase C (PKC), Rho GTPases, matrix metalloprotease 9 (MMP9), and mitogen-activated protein kinases (MAPK).…”

“…In addition, GnRH receptor signaling to ERK in gonadotropes has been shown to incorporate MMP9 activation [ 26 ]. As noted above, AXL receptor activation also promotes ERK- and MMP9-dependent signaling processes [ 16 ]. Despite sharing several common downstream signaling mechanisms, the impact of crosstalk between AXL and GnRH receptors is unclear.…”