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RET as a novel receptor tyrosine kinase of mast cells: autocrine and paracrine activation of RET and its operation in mast cells within the cutaneous microenvironment

Applicant Dr. Magda Babina
Subject Area Dermatology
Immunology
Term from 2016 to 2025
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 323618061
 
Final Report Year 2025

Final Report Abstract

Mast cells (MCs) differentiate in peripheral tissues such as the skin, where they contribute to physiological processes but also serve as key drivers of allergic diseases when dysregulated. The strategies human MCs employ for maturation and survival are incompletely understood. This project aimed to decipher receptor networks governing dermal MCs, with a particular focus on the receptor tyrosine kinases (RTKs) KIT and RET. While KIT has long been recognized as central to MC development, emerging evidence suggested a critical role for RET, which could be confirmed in the course of the project. Focusing first on KIT, the project revealed that its ligand SCF induced extensive changes in the MC phosphoproteome, with over 50% of phosphosites (≈5,400) being regulated. The most active module was Raf/MEK/ERK, followed by PI3K. Notably, ERK and PI3K exhibited functional redundancy in survival protection, while ERK played a unique role in cytokine production. Integrating phosphoproteomic data with additional evidence led us to identify two novel regulators of RTK activity: Capicua (CIC), a transcriptional repressor, and RHEX (c1orf186), a barely characterized signaling component predominantly expressed in MCs. Both proteins inhibited SCF-mediated signaling and survival, albeit through distinct mechanisms. Further exploration of these regulators will be an important avenue for future research. Beyond RTK ligands, alarmins – key markers of perturbed skin – were also examined for their roles as MC-supportive factors. Here, TSLP enhanced survival via STAT5 and JNK pathways, while acute IL-33 stimulation assisted in proliferation, and degranulation, and elicited cytokines on its own. Conversely, chronic IL-33 exposure shifted MCs toward a rather anti-inflammatory phenotype, highlighting the dual nature of this alarmin. Of particular significance was the essential role of the transcription factor CREB in skin MCs. CREB engaged in a feedforward loop with KIT, sustaining RTK function. Its importance was even more pronounced downstream of RET. RET supported MC survival in an autocrine manner via target-derived GDNF. Its inhibition caused severe MC loss, reinforcing RET’s significance alongside KIT. Mechanistically, RET operated via a p38-CREB axis, with both elements being indispensable for native MCs. Surprisingly, RET was required for KIT expression, demonstrating its operation by a dual mechanism, i.e., through both its intrinsic kinase activity and by affording support to KIT. RET expression was highest in native MCs but declined in culture, coinciding with KIT’s dominance. Collectively, the project provided a comprehensive view of MC regulatory networks, establishing RET as a fundamental MC-preserving RTK, CREB as a master regulator, and CIC/RHEX as new modulators of MC signaling. These findings advance our understanding of skin MC biology and may help identify therapeutic targets for MC-related disorders.

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