Epithelial differentiation proceeds in at least two steps: Conversion of a nonepithelial cell into an epithelial sheet followed by terminal differentiation into the mature epithelial phenotype. It was recently discovered that the extracellular matrix (ECM) protein hensin is able to convert a renal intercalated cell line from a flat, squamous shape into a cuboidal or columnar epithelium. Global knockout of hensin in mice results in embryonic lethality at the time that the first columnar cells appear. Here, antibodies that either activate or block integrin 1 were used to demonstrate that activation of integrin ␣v1 causes deposition of hensin in the ECM. Once hensin polymerizes and deposits into the ECM, it binds to integrin ␣6 and mediates the conversion of epithelial cells to a cuboidal phenotype capable of apical endocytosis; therefore, multiple integrins play a role in the terminal differentiation of the intercalated cell: ␣v1 generates polymerized hensin, and another set of integrins (containing ␣6) mediates signals between hensin and the interior of the cells. Epithelia, the earliest differentiated cell type to appear during development, constitute an astonishing variety of phenotypes in all metazoans. The abundant variety of epithelial types suggests that epithelial differentiation must proceed in at least two steps; first, a nonepithelial cell differentiates into a "generic" epithelia, characterized by tight and adherens junctions, transepithelial transport, and polarized distribution of membrane proteins and lipids. During development, these "generic" epithelia terminally differentiate into a mature phenotype characterized by distinct cell shapes, specialized apical structures (e.g., microvilli, microplicae), and specialized functions (apical endocytosis, regulated exocytosis), thus producing a myriad of epithelial phenotypes. 1 Whereas proper terminal differentiation of various epithelial phenotypes is critical for tissue-specific functions, a blockade in epithelial differentiation is thought to cause carcinomas.We had previously found that when rabbits were fed an acid diet, the number of HCO 3 -secreting  intercalated cells decreased while the number of acid-secreting ␣ intercalated cells increased and proposed that the  cell converted to the ␣ form. 2 To study the molecular basis of this, we established a  intercalated conditionally immortalized cell line. 3 This clonal cell line reproduced all of the functions of the  intercalated cell including transepithelial HCO 3 secretion, apical Cl:HCO 3 exchange, and the absence of apical endocytosis; however, despite much effort, the cells did not convert to acid-secreting cells after lowering of the pH of the basolateral me-