Endothelial CD99 signals through soluble adenylyl cyclase and PKA to regulate leukocyte transendothelial migration

Richard L. Watson, Jochen Buck, Lonny R. Levin, Ryan C. Winger, Jing Wang, Hisashi Arase, William A. Muller*

*Corresponding author for this work

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

CD99 is a critical regulator of leukocyte transendothelial migration (TEM). How CD99 signals during this process remains unknown. We show that during TEM, endothelial cell (EC) CD99 activates protein kinase A (PKA) via a signaling complex formed with the lysinerich juxtamembrane cytoplasmic tail of CD99, the A-kinase anchoring protein ezrin, and soluble adenylyl cyclase (sAC). PKA then stimulates membrane trafficking from the lateral border recycling compartment to sites of TEM, facilitating the passage of leukocytes across the endothelium. Pharmacologic or genetic inhibition of EC sAC or PKA, like CD99 blockade, arrests neutrophils and monocytes partway through EC junctions, in vitro and in vivo, without affecting leukocyte adhesion or the expression of relevant cellular adhesion molecules. This is the first description of the CD99 signaling pathway in TEM as well as the first demonstration of a role for sAC in leukocyte TEM.

Original languageEnglish (US)
Pages (from-to)1021-1041
Number of pages21
JournalJournal of Experimental Medicine
Volume212
Issue number7
DOIs
StatePublished - Jun 29 2015

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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