780

DDR1

discoidin domain receptor tyrosine kinase 1;DDR1;discoidin domain receptor tyrosine kinase 1

CD167 antigen-like family member A|PTK3A protein tyrosine kinase 3A|cell adhesion kinase|epithelial discoidin domain-containing receptor 1|mammary carcinoma kinase 10|neuroepithelial tyrosine kinase|neurotrophic tyrosine kinase, receptor, type 4|protein-t

6p21.3

protein-coding

Cell migration plays a central role in processes such as development, wound healing and cancer metastasis. Here we describe a novel interaction between DDR1, a receptor tyrosine kinase activated by collagen, and the phosphoprotein DARPP-32 in mammary epithelial cells. DARPP-32 expression was readily detected in non-transformed mammary cell lines, but was strongly reduced or even absent in breast tumor cell lines, such as MCF7. Transfection of MCF7 cells with DARPP-32 resulted in severely impaired cell migration, while DARPP-32 transfection into the DDR1-deficient breast cancer cell line MDA-MB-231 did not alter migration. Co-expression of both DDR1 and DARPP-32 in MDA-MB-231 cells inhibited migration, thereby supporting a critical role of the DDR1/DARPP-32 complex in motility. mutational substitution of the phosphorylation sites Thr-34 or Thr-75 on DARPP-32 revealed that phosphorylation of Thr-34 is necessary for the ability of DARPP-32 to impair breast tumor cell migration. Thus, DARPP-32 signaling downstream of DDR1 is a potential new target for effective anti-metastatic breast cancer therapy.

Hepatocellular carcinoma (HCC) is highly invasive with a high frequency of recurrence following surgery and poor prognosis. The underlying molecular mechanisms for HCC recurrence are not well understood. Here, we used microarray technology for genome-wide analysis to identify genes who may be involved in tumor recurrence. cDNA from HCC tumor tissues of patients with early recurrence (ER; n = 10) and patients whose HCC had not recurred >/= 2 years postsurgery (nER; n = 10) was hybridized to the Affymetrix Human Geome U133 plus 2.0 whole-genome microarray. Gene clusters were identified and used for hierarchial clustering and principal component analysis. Genes with more than twofold change in expression between ER and nER groups were further analyzed. expression levels of a subset of genes were validated using RT-PCR and immunohistochemistry. A total of 1,646 genes had significantly different expression between the ER and nER groups (P < 0.05) with 61 and 49 genes in the ER upregulated and downregulated for more than twofold in comparison with the nER group, respectively. The cellular functions of differentially expressed genes included cell adhesion, motility, cytoskeleton, transcription, metabolism, signal transduction, and apoptosis. The discoidin domain receptor 1 (DDR1) mRNA expression was significantly higher in the ER (3.36 +/- 0.39) compared with the nER group (3.01 +/- 0.49; P = 0.020). A greater proportion of liver tissue samples from ER versus nER patients had DDR1 protein expression (80.0 vs. 40.0 %, P = 0.022). Using microarray technology, we identified a number of genes whose expression differed between patients with recurrent HCC compared to those without. DD1 mRNA and protein levels were higher in patients with recurrent HCC, suggesting this gene maybe involved in tumor invasion and metastasis.