Cloning

The PINK1 gene was independently cloned by two different groups analyzing differential expression profiles of cancer cell lines. Unoki and Nakamura (3), identified PINK1 following a search for transcriptionally transactivated genes in cell lines overexpressing the phosphatase and tensin homolog (PTEN) gene. Using bioinfor-matic analysis they established that it contained a serine/threonine kinase-like domain, while PINK1 was shown to be downregulated in ovarian tumors they could not demonstrate any growth suppressive effects of PINK1 in an in vitro cancer cell line assay and therefore discontinued characterization of PINK1 in the context of PTEN signaling. Nakajima et al. (4) cloned PINK1 (named BRPK) following a differential expression screen in cell lines of varying metastatic potential. BRPK was consistently overexpressed in the higher metastasizes prompting the authors to characterize it further. They demonstrated that the putative serine/threonine kinase domain was functional by showing that Glutathione S-transferase (GST)-fusion proteins containing either murine or human PINK1 kinase domains were capable of in vitro autophosphorylation. Beilina et al. (5) have subsequently confirmed human PINK1 autophosphorylation in vitro and demonstrated that both a predicted, kinase-dead mutant and several disease-causing missense mutants of PINK1 decreased kinase activity. However, it remains to be determined whether PINK1 phosphory-lates serine or threonine residues and what its natural cellular substrates are.

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