Fc receptor-like 5 inhibits B cell activation via SHP-1 tyrosine phosphatase recruitment

doi:10.1073/pnas.0703354104

Fc receptor-like 5 inhibits B cell activation via SHP-1 tyrosine phosphatase recruitment

Divisions of *Developmental and Clinical Immunology and
^‡Hematology/Oncology and
Departments of ^§Biochemistry and Molecular Genetics,
^¶Medicine,
^†Microbiology, and
^‖Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35294

Contributed by Max D. Cooper, April 16, 2007 (received for review March 13, 2007)

Abstract

The Fc receptor-like protein 5 (FCRL5) on B cells has both an immunoreceptor tyrosine-based activation motif (ITAM)-like sequence and two consensus immunoreceptor tyrosine-based inhibitory motifs (ITIM) in its cytoplasmic region. To evaluate its signaling potential, we expressed constructs for chimeric molecules composed of the cytoplasmic region of FCRL5 and the extracellular and transmembrane regions of the IgG Fc receptor FcγRIIB in a B cell line lacking an endogenous Fc receptor. Coligation of this fusion protein with the B cell receptor (BCR) inhibited BCR-mediated calcium mobilization, intracellular tyrosine phosphorylation, and Erk kinase activation. Our mutational analysis indicated that, whereas tyrosines in both the inhibitory and activation motifs are phosphorylated after ligation, only those in ITIMs influence BCR-mediated signaling. This FCRL5 inhibitory effect was mediated through dual ITIM recruitment of the SH2-containing protein tyrosine phosphatase, SHP-1, which in turn dephosphorylates the ITAM-based tyrosines in BCR Igα/Igβ heterodimers. An FCRL5 inhibitory effect on BCR signaling was likewise demonstrable for primary B cells. Although its ligand is presently unknown, we conclude that FCRL5 has the functional potential to serve as an inhibitory coreceptor on mature B cells in humans.

Footnotes

**To whom correspondence should be addressed. E-mail: max.cooper{at}ccc.uab.edu
Author contributions: C.L.H., G.R.A.E., and M.D.C. designed research; C.L.H. and R.J.B. performed research; R.S.D. contributed new reagents/analytic tools; C.L.H., G.R.A.E., and M.D.C. analyzed data; and C.L.H., R.S.D., and M.D.C. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0703354104/DC1.
Abbreviations:

BCR,

B cell receptor;

PLC,

phospholipase C;

ITIM,

immunoreceptor tyrosine-based inhibitory motif;

ITAM,

immunoreceptor tyrosine-based inhibitory motif;

SH2,

Src homology 2;

SHP,

SH2 domain-containing tyrosine phosphatase;

FCRL5,

Fc receptor-like protein 5;

MM,

multiple myeloma.