DISTINCT STRUCTURAL CHARACTERISTICS OF DISCOIDIN-I SUBFAMILY RECEPTORTYROSINE KINASES AND COMPLEMENTARY EXPRESSION IN HUMAN CANCER

Mammary carcinoma kinase 10 (MCK-10) and colon carcinoma kinase 2 (CCK -2) constitute a subclass of receptor tyrosine kinases characterized b y a discoidin I motif in the extracellular domain and a large cytoplas mic juxtamembrane (JM) region. While the ectodomain structure suggests a common role in cell aggregation, the JM domains of MCK-10 and CCK-2 are structurally most divergent and display features that suggest an involvement in signal generation and definition. MCK-10 occurs in at l east three isoforms, which contain alternatively spliced consensus seq uences for internalization and SH3 domain interaction. The presence of the 37 amino acid insert affects receptor autophosphorylation and cha nges ectodomain glycosylation. Proteolytic cleavage within the extrace llular domain of MCK-10 generates a membrane-anchored kinase domain an d releases a soluble ectodomain fragment including the discoidin I hom ology domain. CCK-2 and MCK-10 expression was found in connective and epithelial tissues, respectively, which in cancers of epithelial origi n results in mutually exclusive expression in stroma and tumor cells, indicating a possible involvement of this class of RTKs in tumor invas ion.