Impaired Abdominal Wall Development and Deficient Wound Healing in Mice Lacking Aortic Carboxypeptidase-Like Protein

Interactions between cells and the extracellular matrix (ECM) are important in the regulation of basic cellular functions, such as proliferation, differentiation, adhesion, and migration (1, 10). These interactions also govern most physiological and pathological processes, including fetal development, angiogenesis, and wound healing. We have identified a novel protein, aortic carboxypeptidase-like protein (ACLP), that is expressed highly in vascular smooth muscle cells of blood vessels, the expression of which increases with smooth muscle cell differentiation (16). The carboxyl terminus of mouse ACLP is identical to that of a cDNA-encoded protein designated adipocyte enhancer binding protein 1 (AEBP1) and reported to be a DNA-binding transcriptional repressor (6). We demonstrated previously that the AEBP1 cDNA is most likely a partial clone of mouse ACLP lacking 410 N-terminal amino acids (16). ACLP contains a domain with similarity to the slime mold protein discoidin I (2). In addition, ACLP contains a signal peptide at its amino terminus and a region with structural similarity to the pro-hormone-processing metallocarboxypeptidases at its carboxyl terminus (5). This structure of tandem discoidin and carboxypeptidase domains also occurs in two proteins related to ACLP, CPX-1 and CPX-2 (17, 28). Like ACLP, CPX-1 and CPX-2 are missing several amino acid residues required for catalytic activity toward standard carboxypeptidase substrates, leading to the hypothesis that these proteins potentially function as binding proteins rather than active carboxypeptidases (28). An additional protein in this subfamily of metallocarboxypeptidases is CPZ. CPZ does not contain a discoidin domain, but instead has a frizzled-like domain at its N terminus (23, 27). Frizzled domains are present in many secreted proteins that modify the Wnt signaling pathway (21, 26). Recently, CPZ was shown to be secreted from cells and to associate with the ECM (19). We hypothesized that ACLP, like other proteins with signal peptides and discoidin domains, is a secreted protein that functions in the extracellular environment. We investigated the subcellular localization of ACLP and analyzed its expression during mouse embryonic development. To elucidate the biological function of ACLP, we targeted the ACLP gene in mice. Here we show that ACLP has an essential role during embryonic development and in adult wound healing processes.