Abstract
The Glial cell line-derived neurotrophic Family Ligands (GFL) are soluble neurotrophic factors that are required for development of multiple human tissues, but which are also important contributors to human cancers. GFL signaling occurs through the transmembrane RET receptor tyrosine kinase, a well-characterized oncogene. GFL-independent RET activation, through rearrangement or point mutations occurs in thyroid and lung cancers. However, GFL-mediated activation of wildtype RET is an increasingly recognized mechanism promoting tumor growth and dissemination of a much broader group of cancers. RET and GFL expression have been implicated in metastasis or invasion in diverse human cancers including breast, pancreatic, and prostate tumors, where they are linked to poorer patient prognosis. In addition to directly inducing tumor growth in these diseases, GFL-RET signaling promotes changes in the tumor microenvironment that alter the surrounding stroma and cellular composition to enhance tumor invasion and metastasis. As such, GFL RET signaling is an important target for novel therapeutic approaches to limit tumor growth and spread and improve disease outcomes.
Highlights
The neurotrophins are a family of soluble neurotrophic factors, originally recognized for their abilities to regulate growth, survival and differentiation of neural-derived cell types
There are four structurally similar family members: Glial Cell-line Derived Neurotrophic Factors (GDNF), neurturin (NRTN), artemin (ARTN), and persephin (PSPN) that are recruited to corresponding non-signaling co-receptors of the GDNF Family Receptors α (GFRα1-4), which are tethered to the plasma membrane through glycosylphosphatidylinositol-anchors (Airaksinen and Saarma, 2002; Figure 1)
GDNF Family Ligands (GFL) and GFRα family members have distinct but overlapping tissue-specific expression patterns that determine their biological roles, all GFL-GFRα complexes signal through a single transmembrane receptor, the RET (REarranged during Transfection) tyrosine kinase (Mulligan, 2014)
Summary
The neurotrophins are a family of soluble neurotrophic factors, originally recognized for their abilities to regulate growth, survival and differentiation of neural-derived cell types. Neurotrophins have well characterized roles as guidance, survival and differentiation factors in developing neurons in the central (CNS) and peripheral nervous systems (PNS) and may promote survival or regrowth of mature neurons, by binding their cell-surface receptors and stimulating downstream signals in their target cells. With the increasing availability of tissue and cell-specific transcriptome and proteome data, it is becoming clear that neurotrophic factors and their receptors are broadly expressed on other, non-neural cell types, where they can contribute to cell growth, differentiation and migration and tissue maturation. The aberrant expression or activation of these signaling complexes can allow these normal growth signals to contribute to the growth or spread of cancer cells, making expression and functions of neurotrophins and their receptors important contributors to human cancer, and potentially valuable therapeutic targets
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