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Endocytic trafficking of GAS6-AXL complexes is associated with sustained AKT activation.
Poswiata, Agata; Kozik, Kamila; Miaczynska, Marta; Zdzalik-Bielecka, Daria.
  • Poswiata A; Laboratory of Cell Biology, International Institute of Molecular and Cell Biology, Warsaw, Poland.
  • Kozik K; Laboratory of Cell Biology, International Institute of Molecular and Cell Biology, Warsaw, Poland.
  • Miaczynska M; Laboratory of Cell Biology, International Institute of Molecular and Cell Biology, Warsaw, Poland. miaczynska@iimcb.gov.pl.
  • Zdzalik-Bielecka D; Laboratory of Cell Biology, International Institute of Molecular and Cell Biology, Warsaw, Poland. dzdzalik@iimcb.gov.pl.
Cell Mol Life Sci ; 79(6): 316, 2022 May 27.
Article in English | MEDLINE | ID: covidwho-1941440
ABSTRACT
AXL, a TAM receptor tyrosine kinase (RTK), and its ligand growth arrest-specific 6 (GAS6) are implicated in cancer metastasis and drug resistance, and cellular entry of viruses. Given this, AXL is an attractive therapeutic target, and its inhibitors are being tested in cancer and COVID-19 clinical trials. Still, astonishingly little is known about intracellular mechanisms that control its function. Here, we characterized endocytosis of AXL, a process known to regulate intracellular functions of RTKs. Consistent with the notion that AXL is a primary receptor for GAS6, its depletion was sufficient to block GAS6 internalization. We discovered that upon receptor ligation, GAS6-AXL complexes were rapidly internalized via several endocytic pathways including both clathrin-mediated and clathrin-independent routes, among the latter the CLIC/GEEC pathway and macropinocytosis. The internalization of AXL was strictly dependent on its kinase activity. In comparison to other RTKs, AXL was endocytosed faster and the majority of the internalized receptor was not degraded but rather recycled via SNX1-positive endosomes. This trafficking pattern coincided with sustained AKT activation upon GAS6 stimulation. Specifically, reduced internalization of GAS6-AXL upon the CLIC/GEEC downregulation intensified, whereas impaired recycling due to depletion of SNX1 and SNX2 attenuated AKT signaling. Altogether, our data uncover the coupling between AXL endocytic trafficking and AKT signaling upon GAS6 stimulation. Moreover, our study provides a rationale for pharmacological inhibition of AXL in antiviral therapy as viruses utilize GAS6-AXL-triggered endocytosis to enter cells.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Proto-Oncogene Proteins / Receptor Protein-Tyrosine Kinases / Intercellular Signaling Peptides and Proteins / Endocytosis Type of study: Prognostic study Limits: Humans Language: English Journal: Cell Mol Life Sci Journal subject: Molecular Biology Year: 2022 Document Type: Article Affiliation country: S00018-022-04312-3

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Proto-Oncogene Proteins / Receptor Protein-Tyrosine Kinases / Intercellular Signaling Peptides and Proteins / Endocytosis Type of study: Prognostic study Limits: Humans Language: English Journal: Cell Mol Life Sci Journal subject: Molecular Biology Year: 2022 Document Type: Article Affiliation country: S00018-022-04312-3