CD318 (also known as CDCP1, TRASK, SIMA135, or gp140) is a cell-surface glycoprotein with an apparent molecular mass of ∼140 kDa. It consists of three extracellular CUB domains, a transmembrane domain, and an intracellular domain. CD318 can be proteolytically cleaved between the two distal CUB domains by certain serine proteases, resulting in different ratios of the ∼140-kDa intact molecule and the ∼80-kDa cleaved product on various cells. Cleaved CD318 is phosphorylated and activated by Src kinase, then the activated CD318 forms a complex with activated β1 integrin and activates FAK/PI3K/Akt motility signaling to promote early tumor dissemination. Under normal conditions, CD318 is present on many epithelial cells, some hematopoietic cells (18), and mesenchymal stem cells. CD318 is also present on many tumor cells. Up-regulation of CD318 expression is associated with a poor prognosis for many cancer patients.