Role of NEK6 in tumor promoter-induced transformation in JB6 C141 mouse skin epidermal cells.
NEK6 (NIMA-related kinase 6) is a homologue of the Aspergillus nidulans protein NIMA (never in mitosis, gene A). We demonstrate that overexpression of NEK6 induces anchorage-independent transformation of JB6 Cl41 mouse epidermal cells. Tissue arrays and Western immunoblot analysis show that NEK6 is overexpressed in malignant tissues and several cancer cell lines. Our data also show that NEK6 interacts with STAT3, an oncogenic transcription factor, and phosphorylates STAT3 on Ser(727), which is important for transcriptional activation. Additional studies using NEK6 mutants suggested that the phosphorylation on both Ser(206) and Thr(210) of NEK6 is critical for STAT3 phosphorylation and anchorage-independent transformation of mouse epidermal cells. Notably, knockdown of NEK6 decreased colony formation and STAT3 Ser(727) phosphorylation. Based on our findings, the most likely mechanism that can account for this biological effect involves the activation of STAT3 through the phosphorylation on Ser(727). Because of the critical role that STAT3 plays in mediating oncogenesis, the stimulatory effects of NEK6 on STAT3 and cell transformation suggest that this family of serine/threonine kinases might represent a novel chemotherapeutic target.
Jeon
Young Jin
YJ
The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.
Lee
Kun Yeong
KY
Cho
Yong-Yeon
YY
Pugliese
Angelo
A
Kim
Hong Gyum
HG
Jeong
Chul-Ho
CH
Bode
Ann M
AM
Dong
Zigang
Z
D019943:Amino Acid Substitution; D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D004817:Epidermis / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D000072379:NIMA-Related Kinases; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
D050796:STAT3 Transcription Factor; D000072379:NIMA-Related Kinases; C442331:NIMA-related kinase 6; D017346:Protein Serine-Threonine Kinases