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Trop-2 is a novel calcium signal transducer expressed at high levels by most human carcinomas. To develop an animal model to study the function of this molecule in vivo, we have cloned the murine Trop2 gene. Using human TROP2 primers, we amplified by PCR a segment of murine Trop2. This was used as a probe to clone a full-length gene by hybridization of a genomic library. The cloned murine Trop2 gene is functional, as indicated by sequencing and by expression after transfection. The murine Trop2 is 87.4% similar to its human homologue, with the highest conservation in the extracellular region between residues 86 and 157. Essentially all cysteines are conserved between the human and the murine genes, suggesting conservation of the Trop2 disulfide bridges and of its overall structure. Intriguingly, the cytoplasmic tail of Trop2 shows a highly conserved phosphatidylinositol 4,5-bisphosphate (PIP2)-binding sequence, which overlaps with a protein kinase C phosphorylation site. Thus, we speculate that PIP2 might regulate the phosphorylation state of Trop2 and play a role in its signal transduction. Murine Trop2 mRNA is detected in normal kidney, lung, ovary and testis, similarly to the human gene. Interestingly, the highest levels of expression are found in immortalized keratinocytes. Since Trop2 is undetectable in undifferentiated spindle cell carcinomas, this suggests a preferential expression at early stages of tumor progression.