The CD20 homologue MS4A4 directs trafficking of KIT toward clathrin-independent endocytosis pathways and thus regulates receptor signaling and recycling.

Abstract

MS4A family members differentially regulate the cell cycle, and aberrant, or loss of, expression of MS4A family proteins has been observed in colon and lung cancer. However, the precise functions of MS4A family proteins and their mechanistic interactions remain unsolved. Here we report that MS4A4 facilitates trafficking of the receptor tyrosine kinase KIT through endocytic recycling rather than degradation pathways by a mechanism that involves recruitment of KIT to caveolin-1-enriched microdomains. Silencing of MS4A4 in human mast cells altered ligand-induced KIT endocytosis pathways and reduced receptor recycling to the cell surface, thus promoting KIT signaling in the endosomes while reducing that in the plasma membrane, as exemplified by Akt and PLCγ1 phosphorylation, respectively. The altered endocytic trafficking of KIT also resulted in an increase in SCF-induced mast cell proliferation and migration, which may reflect altered signaling in these cells. Our data reveal a novel function for MS4A family proteins in regulating trafficking and signaling, which could have implications in both proliferative and immunological diseases.

• Authors: Glenn Cruse, Michael A Beaven, Stephen C Music, Peter Bradding, Alasdair M Gilfillan, Dean D Metcalfe
• Journal: Molecular biology of the cell (Mol Biol Cell) Vol. 26 Issue 9 Pg. 1711-27 (May 01 2015) ISSN: 1939-4586 [Electronic] United States
• PMID: 25717186 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
• Copyright: © 2015 Cruse et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

Chemical References

• Antigens, CD20
• Clathrin
• MS4A4A protein, human
• Membrane Proteins
• Proto-Oncogene Proteins c-kit
• Phospholipase C gamma
• RAB5C protein, human
• rab5 GTP-Binding Proteins

Topics

• Antigens, CD20 (physiology)
• Cell Line
• Cell Membrane (metabolism)
• Clathrin (metabolism)
• Endocytosis
• Endosomes (metabolism)
• Gene Expression
• Humans
• Mast Cells (metabolism)
• Membrane Proteins (physiology)
• Phospholipase C gamma (metabolism)
• Phosphorylation
• Protein Processing, Post-Translational
• Protein Transport
• Proto-Oncogene Proteins c-kit (metabolism)
• Signal Transduction
• rab5 GTP-Binding Proteins (metabolism)