In previous reports, we described that DPC4/Smad4 and Smad2 are mutated in a fraction of human lung cancers and suggested possible roles of the downstream mediators of transforming growth factor-beta (TGF-beta)-elicited signals in the pathogenesis of this most common cancer. In the present study, we investigated whether another downstream mediator, human TGF-beta-activated kinase I (hTAKI), also is altered in lung cancer. For this purpose, the hTAKI gene was cloned with the aid of an expression sequence tag database search and cDNA library screening, and hTAKI was found to be expressed ubiquitously in 2 distinct isoforms regulated in a tissue-specific manner in fetal and adult normal tissues. Interestingly, hTAKI was assigned to the chromosome region 6q14-21, which is deleted frequently in various human malignancies, including lung cancer. Despite our extensive search for alterations in 39 lung cancer specimens as well as in 16 lung cancer cell lines, somatic mutations of hTAKI were not identified, indicating that hTAKI itself is not a frequent target for genetic alterations in lung cancer. (C) 1998 Wiley-Liss, Inc.