T-cadherin is a receptor for hexameric and high-molecular-weight forms of Acrp30/adiponectin.
Acrp30/adiponectin is reduced in the serum of obese and diabetic individuals, and the genetic locus of adiponectin is linked to the metabolic syndrome. Recombinant adiponectin, administered to diet-induced obese mice, induced weight loss and improved insulin sensitivity. In muscle and liver, adiponectin stimulates AMP-activated protein kinase activation and fatty acid oxidation. To expression-clone molecules capable of binding adiponectin, we transduced a C2C12 myoblast cDNA retroviral expression library into Ba/F3 cells and panned infected cells on recombinant adiponectin linked to magnetic beads. We identified T-cadherin as a receptor for the hexameric and high-molecular-weight species of adiponectin but not for the trimeric or globular species. Only eukaryotically expressed adiponectin bound to T-cadherin, implying that posttranslational modifications of adiponectin are critical for binding. An adiponectin mutant lacking a conserved N-terminal cysteine residue required for formation of hexamer and high-molecular-weight species did not bind T-cadherin in coimmunoprecipitation studies. Although lacking known cellular functions, T-cadherin is expressed in endothelial and smooth muscle cells, where it is positioned to interact with adiponectin. Because T-cadherin is a glycosylphosphatidylinositol-anchored extracellular protein, it may act as a coreceptor for an as-yet-unidentified signaling receptor through which adiponectin transmits metabolic signals.
Hug
Christopher
C
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Wang
Jin
J
Ahmad
Naina Shehzeen
NS
Bogan
Jonathan S
JS
Tsao
Tsu-Shuen
TS
Lodish
Harvey F
HF
D052242:Adiponectin; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D006224:Cricetinae; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007668:Kidney / Q000166:cytology; D008024:Ligands; D008280:Magnetics; D051379:Mice; D008970:Molecular Weight; D032446:Myoblasts / Q000166:cytology; D010957:Plasmids; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D052242:Adiponectin; D015820:Cadherins; C099972:H-cadherin; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D011506:Proteins