title: TLT-1s, alternative transcripts of triggering receptor expressed on myeloid cell-like transcript-1 (TLT-1), Inhibits the triggering receptor expressed on myeloid cell-2 (TREM-2)-mediated signaling pathway during osteoclastogenesis.
abstract: Triggering receptor expressed on myeloid cells (TREM)-like transcript-1 (TLT-1) is an immunoreceptor tyrosine-based inhibitory motif (ITIM)-baring TREM family protein. In this study, we identified an alternative transcript form of TLT-1, namely TLT-1s, which has very short extracellular immunoglobulin domain consisting of only 202 amino acids. TLT-1s was mainly expressed in macrophages and osteoclast precursor cells. Upon receptor activator of nuclear factor-κB ligand stimulation, TLT-1s mRNA and protein levels were gradually decreased in BMMs. We also showed the TLT-1s is localized to the cytoplasmic membrane in osteoclast precursor cells. TLT-1s silencing strongly enhanced the formation and resorption activity of osteoclast. In addition, forced expression of TLT-1s showed reduced formation of osteoclast. Because ITIM-baring proteins inhibit immunoreceptor tyrosine-based activation motif (ITAM)-mediated receptor signaling, we tested whether TLT-1s physically interacted with TREM-2, the ITAM-associated co-stimulatory receptor essential for osteoclast differentiation. We showed that TLT-1s is associated with TREM-2 in osteoclast precursor cells. TLT-1s is also associated with tyrosine Src homology 2 domain-containing phosphatase-1 and SH2 domain-containing inositol phosphatase-1 and recruited them to the TREM2-ITAM signaling complex. In addition, knockdown of TLT-1s markedly elevated the intracellular calcium concentration and oscillation in osteoclast precursor cells. In addition, calcium-mediated induction of nuclear factor of activated T cells was also increased by TLT-1s silencing. Furthermore, TREM-2-mediated Akt activation and proliferation of osteoclast precursor cells were also enhanced in TLT-1s silenced cells. In this paper, we found the noble ITIM-baring inhibitory membrane protein; TLT-1s, which regulates ITAM-mediated signaling on osteoclastogenesis.
authors: Department of Cell and Developmental Biology, BK21 and DRI, Seoul National University, Seoul, Korea.
authors: Soo-Hyun
authors: SH
authors: Yoon
authors: Yong Deok
authors: YD
authors: Lee
authors: Jeongim
authors: J
authors: Ha
authors: Youngkyun
authors: Y
authors: Lee
authors: Hong-Hee
authors: HH
authors: Kim
mesh_terms: D017398:Alternative Splicing / Q000502:physiology*; D020816:Amino Acid Motifs; D000818:Animals; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000502:physiology; D020868:Gene Silencing; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D018909:src Homology Domains
chemical_list: D008562:Membrane Glycoproteins; D016328:NF-kappa B; D012333:RNA, Messenger; D011971:Receptors, Immunologic; C498716:Trem2 protein, mouse; C471763:Treml1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D010749:Phosphoprotein Phosphatases