CDO: An Oncogene-, Serum-, and Anchorage-regulated Member of the Ig/Fibronectin Type III Repeat Family

Abstract

Cell adhesion molecules of the Ig superfamily are implicated in a wide variety of biological processes, including cell migration, axon guidance and fasciculation, and growth control and tumorigenesis. Expression of these proteins can be highly dynamic and cell type specific, but little is known of the signals that regulate such specificity. Reported here is the molecular cloning and characterization of rat CDO, a novel cell surface glycoprotein of the Ig superfamily that contains five Ig-like repeats, followed by three fibronectin type III–like repeats in its extracellular region, and a 256-amino acid intracellular region that does not resemble other known proteins. In rat embryo fibroblasts, cdo mRNA expression is maximal in confluent, quiescent cells. It is rapidly and transiently down-regulated by serum stimulation of such cells, and is constitutively down-regulated in oncogene-transformed derivatives of these cells. CDO protein levels are also dramatically regulated by cell–substratum adhesion, via a mechanism that is independent of cdo mRNA expression. The amount of CDO produced at the surface of a cell may therefore be governed by a complex balance of signals, including mitogenic stimuli that regulate cdo mRNA levels, and substratum-derived signals that regulate CDO protein production. cdo mRNA is expressed at low levels in most adult rat tissues. A closely related human gene maps to chromosome 11q23–24, a region that displays frequent loss of heterozygosity in human lung, breast, and ovarian tumors. Taken together, these data suggest that loss of CDO function could play a role in oncogenesis.

Cloning and expression of three zebrafish roundabout homologs suggest roles in axon guidance and cell migration

“…Yuan et al, 1999). Second, they are much more similar to DRobo1 (Kidd et al, 1998a) and its C. elegans homolog, Sax-3 (Zallen et al, 1998) than they are to the human CDO protein, which also has a 5 IG ϩ 3 FN extracellular structure but is not a Robo family member (Kang et al, 1997). This IG domain analysis (Fig.…”

“…Robo1 and Robo2 are closest to HRobo1 and RRobo2, respectively, while Robo3 is equally distant from HRobo1, RRobo2, and MRig-1. HCDO is a human protein that also has a 5 IG ϩ 3 FN extracellular structure but is not a Robo family member (Kang et al, 1997). C: Comparison of cytoplasmic motifs among Robo family members.…”

N-cadherin ligation, but not Sonic hedgehog binding, initiates Cdo-dependent p38α/β MAPK signaling in skeletal myoblasts

“…Cdo is a multifunctional cell surface protein with Ig and FnIII repeats in its ectodomain and a long intracellular region that does not resemble other proteins (9). During myoblast differentiation, the Cdo intracellular region is bound by Bnip-2, a scaffold protein for the small GTPase, Cdc42, and by JLP, a scaffold protein for the p38 pathway (6,7).…”

Structure of a heparin-dependent complex of Hedgehog and Ihog

“…Ihog is homologous to another Drosophila protein, CG32796 or brother of Ihog (BOI), and two mammalian proteins, CDO and BOC (18,19), that are also components of the Hh signaling pathway (11,20,21). Several observations indicate that Ihog may function as a coreceptor for Hh: (i) reduction of Ihog expression results in diminished Hh binding and responsiveness, (ii) epistasis experiments place Ihog function upstream or at the level of Ptc, (iii) the Ihog extracellular region is able to pull down HhN from conditioned medium, and (iv) coexpression of Ptc and Ihog results in a synergistic increase in Hh binding to the cell surface (11).…”