| CUB-domain–containing protein 1 (CDCP1) is a type I transmembrane glycoprotein with three extracellular CUB domains that position it within adhesion and signaling networks at the plasma membrane, where it acts as a scaffold integrating tyrosine kinase and growth factor pathways important for anchorage, migration and survival. The extracellular CUB modules support interactions with matrix and soluble ligands, including direct binding to transforming growth factor β1 (TGF‑β1), while the short intracellular tail carries multiple tyrosine residues that become phosphorylated by Src family kinases, creating docking sites for effectors such as Src and PKCδ and linking CDCP1 to cytoplasmic signaling complexes. Loss of cell adhesion or detachment induces phosphorylation of key tyrosines, notably Tyr707 and Tyr806, by Src family kinases, and phosphorylated CDCP1 recruits and activates Src in lipid microdomains, which elevates global phosphotyrosine content and promotes anchorage‑independent growth and survival in breast and other solid tumor cell lines. CDCP1 signaling regulates anoikis resistance, migration and extracellular matrix degradation in a tyrosine phosphorylation–dependent manner, and knockdown of CDCP1 blocks tumor metastasis or peritoneal dissemination without markedly affecting proliferation, indicating a specific role in invasive and disseminative steps of the metastatic cascade. Proteolytic cleavage of the ectodomain by plasmin-like serine proteases generates a truncated, phosphorylated form that transduces outside‑in signals facilitating early tumor dissemination; antibody blockade of cleaved CDCP1 enhances apoptosis of disseminated tumor cells and reduces colonization in experimental metastasis models. Direct binding of the CUB domains to TGF‑β1 increases TGF‑β/Smad2 reporter activity and Smad2 phosphorylation without requiring Src or PKCδ, implicating CDCP1 as a co-receptor that amplifies TGF‑β1 signaling and potentially cooperates with TGF‑β pathways in cancer progression. At the network level, CDCP1 sits at the intersection of SRC/PKCδ, PI3K/AKT, RAS/ERK and Wnt/β‑catenin axes as well as metabolic circuits such as the oxidative pentose phosphate pathway and fatty acid oxidation, and its elevated expression in malignancies of breast, lung, colorectum, ovary, kidney, liver, pancreas and hematopoietic system correlates with progressive disease and poor survival. In hematopoiesis, CDCP1 is expressed on CD34⁺CD38⁻ bone marrow stem/progenitor cells, cord blood and mobilized peripheral blood stem cells, as well as on CD34⁺CD133⁺ myeloid leukemic blasts, and stimulation of CD34⁺ cells with CDCP1‑reactive antibody increases erythroid colony formation, establishing CDCP1 as a marker for immature hematopoietic subsets with a functional role in early hematopoiesis. |
