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Distinct structural characteristics of discoidin I subfamily receptor tyrosine kinases and complementary expression
1Department of Molecular Biology, Max-Planck-Institute für Biochemie, Martinsried, Germany.
Abstract:
Mammary carcinoma kinase 10 (MCK-10) and colon carcinoma kinase 2 (CCK-2) constitute a subclass of receptor tyrosine kinases characterized by a discoidin I motif in the extracellular domain and a large cytoplasmic 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 least three isoforms, which contain alternatively spliced consensus sequences for internalization and SH3 domain interaction. The presence of the 37 amino acid insert affects receptor autophosphorylation and changes ectodomain glycosylation. Proteolytic cleavage within the extracellular domain of MCK-10 generates a membrane-anchored kinase domain and releases a soluble ectodomain fragment including the discoidin I homology domain. CCK-2 and MCK-10 expression was found in connective and epithelial tissues, respectively, which in cancers of epithelial origin results in mutually exclusive expression in stroma and tumor cells, indicating a possible involvement of this class of RTKs in tumor invasion.
Insights
Mammary carcinoma kinase 10 (MCK-10) and colon carcinoma kinase 2 (CCK-2) are receptor tyrosine kinases involved in cell aggregation. Their distinct juxtamembrane regions suggest roles in signal generation, with implications for tumor invasion.
Area of Science:
- Molecular Biology
- Cell Signaling
- Cancer Research
Background:
- Mammary carcinoma kinase 10 (MCK-10) and colon carcinoma kinase 2 (CCK-2) are receptor tyrosine kinases (RTKs) with a discoidin I motif and large juxtamembrane (JM) regions.
- The ectodomain suggests cell aggregation roles, while divergent JM domains imply involvement in signal generation and definition.
Purpose of the Study:
- To investigate the structural and functional characteristics of MCK-10 and CCK-2.
- To explore the implications of their expression patterns in epithelial cancers.
Main Methods:
- Analysis of MCK-10 isoforms and their alternatively spliced sequences.
- Investigation of the effects of a 37 amino acid insert on MCK-10 autophosphorylation and glycosylation.
- Characterization of proteolytic cleavage within the MCK-10 extracellular domain.
- Examination of CCK-2 and MCK-10 expression in various tissues.
Main Results:
- MCK-10 exists in at least three isoforms with sequences affecting internalization and SH3 domain interaction.
- A 37 amino acid insert in MCK-10 impacts autophosphorylation and ectodomain glycosylation.
- Proteolytic cleavage of MCK-10 yields a membrane-anchored kinase domain and a soluble ectodomain fragment.
- MCK-10 and CCK-2 show expression in epithelial and connective tissues, respectively.
Conclusions:
- The divergent JM domains of MCK-10 and CCK-2 suggest specialized roles in signal generation.
- Mutually exclusive expression in stroma and tumor cells of epithelial cancers indicates a potential role for these RTKs in tumor invasion.