CMRF-35-like molecule-1, a novel mouse myeloid receptor, can inhibit osteoclast formation.
By homology to triggering receptor expressed by myeloid cells-2, we screened the mouse expressed sequence tag database and isolated a new single Ig domain receptor, which we have expressed and characterized. The receptor is most similar in sequence to the human CMRF-35 receptor, and thus we have named it CMRF-35-like molecule (CLM)-1. By screening the mouse genome, we determined that CLM-1 was part of a multigene family located on a small segment of mouse chromosome 11. Each contains a single Ig domain, and they are expressed mainly in cells of the myeloid lineage. CLM-1 contains multiple cytoplasmic tyrosine residues, including two that lie in consensus immunoreceptor tyrosine-based inhibitory motifs, and we demonstrate that CLM-1 can associate with Src-homology 2 containing phosphatase-1. Expression of CLM-1 mRNA is down-regulated by treatment with receptor activator of NF-kappaB ligand (RANKL), a cytokine that drives osteoclast formation. Furthermore, expression of CLM-1 in the osteoclastogenic cell line RAW (RAW.CLM-1) prevents osteoclastogenesis induced by RANKL and TGF-beta. RAW.CLM-1 cells fail to multinucleate and do not up-regulate calcitonin receptor, but they express tartrate-resistant acid phosphatase, cathepsin K, and beta(3) integrin, suggesting that osteoclastogenesis is blocked at a late-intermediate stage. Thus, we define a new family of myeloid receptors, and demonstrate that the first member of this family, CLM-1, is an inhibitory receptor, able to block osteoclastogenesis.
Chung
Dong-Hui
DH
Veterans Administration Medical Center and University of California, San Francisco, CA 94121, USA.
Humphrey
Mary Beth
MB
Nakamura
Mary C
MC
Ginzinger
David G
DG
Seaman
William E
WE
Daws
Michael R
MR
D000595:Amino Acid Sequence; D000818:Animals; D000954:Antigens, Surface / Q000737:chemistry*; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D006131:Growth Inhibitors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D007136:Immunoglobulins / Q000737:chemistry; D047908:Intracellular Signaling Peptides and Proteins; D007941:Leukemia P388; D008562:Membrane Glycoproteins / Q000737:chemistry*; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000276:immunology; D022423:Myeloid Cells / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000276:immunology*; D054645:Protein Phosphatase 1; D017434:Protein Structure, Tertiary; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D017386:Sequence Homology, Amino Acid
D000954:Antigens, Surface; C444139:CD300C protein, human; C482560:CLM-1 protein, mouse; D006131:Growth Inhibitors; D007136:Immunoglobulins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D054645:Protein Phosphatase 1; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C509248:Ptpn6 protein, mouse