A Pseudokinase Receptor Prevents Death of Colon Cancer Cells

Abolishing the activity of a pseudokinase enzyme in the intestinal tissue of mice with colorectal cancer stimulated the apoptosis of cancer cells and the shrinkage of tumors.

Investigators from the University of North Carolina (Chapel Hill, USA) worked with the ApcMin mouse model of colon cancer. Their intent was to study the potential usefulness of drugs directed at the epidermal growth factor receptor (EGFR) and related receptors expressed by the cancer cells. They reported in the August 17, 2009, online edition of the Journal of Clinical Investigation that by genetically engineering the ApcMin mice to lack the gene for a receptor called ERBB3, they were able to induce apoptosis of the cancer cells and nearly complete elimination of the tumors.

The protein ERBB3 (V-erb-b2 erythroblastic leukemia viral oncogene homolog 3) is a member of the EGFR family of receptor tyrosine kinases. This membrane-bound protein has a neuregulin-binding domain but not an active kinase domain. It therefore can bind this ligand but not convey the signal into the cell through protein phosphorylation. However, it does form heterodimers with other EGF receptor family members that do have kinase activity. Heterodimerization leads to the activation of pathways, which lead to cell proliferation or differentiation. Amplification of this gene and/or overexpression of its protein have been reported in numerous cancers, including prostate, bladder, and breast tumors. It is thought that ERBB3, when activated, becomes a substrate for dimerization and subsequent phosphorylation by ERBB1, ERBB2, and ERBB4.

"If you genetically remove ERBB3, as you would if you were pharmacologically targeting it, then the mice rarely develop colon cancer,” said senior author Dr. David Threadgill, professor of genetics at the University of North Carolina. "So, ERBB3 is essential for preventing colon cancer cells from dying. If we can use an inhibitor to block ERBB3, then it should be a very potent anticancer therapeutic. This study shows that targets that historically had not been considered because they do not have the typical activities of a kinase can be equally if not more important in supporting cancer cells.”

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