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• W2058004911 abstract "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 Ser727, which is important for transcriptional activation. Additional studies using NEK6 mutants suggested that the phosphorylation on both Ser206 and Thr210 of NEK6 is critical for STAT3 phosphorylation and anchorage-independent transformation of mouse epidermal cells. Notably, knockdown of NEK6 decreased colony formation and STAT3 Ser727 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 Ser727. 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. 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 Ser727, which is important for transcriptional activation. Additional studies using NEK6 mutants suggested that the phosphorylation on both Ser206 and Thr210 of NEK6 is critical for STAT3 phosphorylation and anchorage-independent transformation of mouse epidermal cells. Notably, knockdown of NEK6 decreased colony formation and STAT3 Ser727 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 Ser727. 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. IntroductionNEK6 (NIMA-related kinase 6) is a serine/threonine kinase identified as a homologue of the Aspergillus nidulans protein NIMA (never in mitosis, gene A). Aspergillus NIMA is essential for the initiation of mitosis, and its degradation is necessary for mitotic exit (1Osmani S.A. May G.S. Morris N.R. J. Cell Biol. 1987; 104: 1495-1504Crossref PubMed Scopus (228) Google Scholar, 2Pu R.T. Osmani S.A. EMBO J. 1995; 14: 995-1003Crossref PubMed Scopus (73) Google Scholar). The NEK6 protein level is also increased during mitosis, concomitant with an increase in NEK6 activity (3Belham C. Roig J. Caldwell J.A. Aoyama Y. Kemp B.E. Comb M. Avruch J. J. Biol. Chem. 2003; 278: 34897-34909Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar). Overexpression of catalytically inactive NEK6 causes arrest of cells in mitosis and interferes with chromosome segregation (4Yin M.J. Shao L. Voehringer D. Smeal T. Jallal B. J. Biol. Chem. 2003; 278: 52454-52460Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). Furthermore, depletion of the endogenous NEK6 protein using siRNA in HeLa cells resulted in mitotic arrest followed by apoptosis (4Yin M.J. Shao L. Voehringer D. Smeal T. Jallal B. J. Biol. Chem. 2003; 278: 52454-52460Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). Therefore, NEK6 activity appears to be required for proper anaphase progression with cells either arresting at the spindle checkpoint and undergoing apoptosis or completing mitosis but with the acquisition of nuclear abnormalities in the process. Inhibition of NEK6 has been suggested to be involved in G2/M phase cell cycle arrest induced by DNA damage (5Lee M.Y. Kim H.J. Kim M.A. Jee H.J. Kim A.J. Bae Y.S. Park J.I. Chung J.H. Yun J. Cell Cycle. 2008; 7: 2705-2709Crossref PubMed Scopus (42) Google Scholar).Despite the critical role of NEK6 in maintaining proper progression of the cell cycle, the physiological substrates of NEK6 are largely undefined. NEK6 was initially identified in a screen to determine upstream kinases of the 70 ribosomal S6 kinase (6Belham C. Comb M.J. Avruch J. Curr. Biol. 2001; 11: 1155-1167Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar). However, additional evidence did not support S6 kinase as a physiological substrate of NEK6 (7Lizcano J.M. Deak M. Morrice N. Kieloch A. Hastie C.J. Dong L. Schutkowski M. Reimer U. Alessi D.R. J. Biol. Chem. 2002; 277: 27839-27849Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar). NEK6 was suggested to phosphorylate the kinesin Eg5 at a novel site necessary for mitotic spindle formation (8Rapley J. Nicolàs M. Groen A. Regué L. Bertran M.T. Caelles C. Avruch J. Roig J. J. Cell Sci. 2008; 121: 3912-3921Crossref PubMed Scopus (97) Google Scholar).A possible role for NEK6 in tumorigenesis has been indicated. Analysis of hepatic cancer carcinomas showed that nek6 mRNA expression was up-regulated in 70% of all cancers examined and correlated well with the up-regulation of peptidyl-prolyl isomerase or Pin1 (9Chen J. Li L. Zhang Y. Yang H. Wei Y. Zhang L. Liu X. Yu L. Biochem. Biophys. Res. Commun. 2006; 341: 1059-1065Crossref PubMed Scopus (34) Google Scholar). Because Pin1 plays an important role in the regulation of cell cycle and is prevalently overexpressed in human cancers, it is regarded as a new potential therapeutic target. Furthermore, evidence indicates that the growth rate of MDA-MB-231 human breast cancer cells is reduced by the overexpression of catalytically inactive NEK6 (4Yin M.J. Shao L. Voehringer D. Smeal T. Jallal B. J. Biol. Chem. 2003; 278: 52454-52460Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). However, the biological functions and mechanisms of NEK6 activity in carcinogenesis are largely unknown. Thus, the identification of key substrates is probably the most important component in discovering the function of NEK6 in carcinogenesis.In the present study, we demonstrate that NEK6 is overexpressed in various human cancer tissues, and ectopic expression of NEK6 increases tumor promoter-induced transformation of JB6 Cl41 mouse epidermal cells. We also discovered that STAT3, a member of the signal transducers and activators of transcription (STAT) family, is a novel target of NEK6. STAT3, which was originally discovered as a mediator in the cytokine signaling pathway, plays an important role in carcinogenesis, including anchorage-independent transformation of JB6 Cl41 cells (10Yu C.Y. Wang L. Khaletskiy A. Farrar W.L. Larner A. Colburn N.H. Li J.J. Oncogene. 2002; 21: 3949-3960Crossref PubMed Scopus (34) Google Scholar). Taken together, these results provide strong evidence linking NEK6 to carcinogenesis.DISCUSSIONWe demonstrated that ectopic expression of NEK6 increases tumor promoter-induced cell transformation and STAT3 phosphorylation at Ser727. The major finding of the present study is that NEK6 plays an important role in oncogenesis. Using the JB6 Cl41 cell transformation model, we showed that ectopic expression of NEK6 significantly increases the anchorage-independent growth induced by EGF or TPA. The expression of kinase-inactive NEK6 further confirmed the important role of NEK6 in tumor promoter-induced cell transformation. The function of NEK6 in cancer cell growth was suggested by a previous report indicating that the growth rate of MDA-MB-231 human breast cancer cells was reduced by the overexpression of catalytically inactive NEK6 (4Yin M.J. Shao L. Voehringer D. Smeal T. Jallal B. J. Biol. Chem. 2003; 278: 52454-52460Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). Our data also confirmed that NEK6 wild type or mutant K74M/K75M expression in JB6 Cl41 cells increased or decreased cell proliferation, respectively (Fig. 2B). Moreover, immunofluorescence staining of 47 pairs of normal and cancer tissues showed that the NEK6 protein was highly abundant in cancer tissues compared with normal tissues (Fig. 1). Chen et al. (9Chen J. Li L. Zhang Y. Yang H. Wei Y. Zhang L. Liu X. Yu L. Biochem. Biophys. Res. Commun. 2006; 341: 1059-1065Crossref PubMed Scopus (34) Google Scholar) also demonstrated that NEK6 mRNA expression was up-regulated in 70% of hepatic carcinomas. These results highlight the potential of NEK6 as a novel target of chemotherapeutic and chemopreventive agents.We also showed that STAT3, an oncogenic transcription factor, is a novel target of NEK6 and an important mediator of oncogenesis by NEK6. Several lines of experimental evidence support this contention. First, when we tested the interaction between NEK6 and several transcription factors that are important in tumorigenesis or tumor suppression, we found that STAT3 is a strong binding partner of NEK6. Second, we showed that NEK6 phosphorylated STAT3 in a dose-dependent manner. Third, knockdown of NEK6 decreased STAT3 phosphorylation. Finally, based on the mutant NEK6 study, NEK6-mediated STAT3 Ser727 phosphorylation corresponds well with JB6 Cl41 cell transformation.STAT3 is a member of the STAT family of cytoplasmic transcription factors, which play critical roles in cytokine and growth factor signaling. Activated STAT3 induces transformation of NIH-3T3 cells and produces tumors in nude mice (13Bromberg J.F. Wrzeszczynska M.H. Devgan G. Zhao Y. Pestell R.G. Albanese C. Darnell Jr., J.E. Cell. 1999; 98: 295-303Abstract Full Text Full Text PDF PubMed Scopus (2472) Google Scholar, 26Bromberg J.F. Horvath C.M. Besser D. Lathem W.W. Darnell Jr., J.E. Mol. Cell Biol. 1998; 18: 2553-2558Crossref PubMed Scopus (568) Google Scholar). Constitutive activation of STAT3 is detected in many human malignancies, including prostate, lung, brain, breast, and squamous cell carcinomas. Persistent STAT3 activation promotes uncontrolled growth and survival through deregulation of gene expression, including cyclin D1, c-myc, bcl-xL, mcl-1, and survivin genes, and thereby contributes to oncogenesis. Because of the critical role of STAT3 in oncogenesis, the stimulatory effects of NEK6 on anchorage-independent transformation of JB6 Cl41 mouse skin cells most likely involve the activation of STAT3. This was further confirmed by a report showing that STAT3 plays an important role in carcinogenesis, including anchorage-independent transformation of JB6 Cl41 cells (10Yu C.Y. Wang L. Khaletskiy A. Farrar W.L. Larner A. Colburn N.H. Li J.J. Oncogene. 2002; 21: 3949-3960Crossref PubMed Scopus (34) Google Scholar).One of the major findings of the present study is that the phosphorylation on both Ser206 and Thr210 of NEK6 is critical for STAT3 phosphorylation and anchorage-independent transformation of mouse epidermal cells. The importance of Ser206 was previously described in that Nercc/NEK9 catalyzes the direct phosphorylation of prokaryotic recombinant NEK6 at Ser206 in vitro, concomitant with a 20–25-fold activation of NEK6 activity toward S6 kinase phosphorylation (3Belham C. Roig J. Caldwell J.A. Aoyama Y. Kemp B.E. Comb M. Avruch J. J. Biol. Chem. 2003; 278: 34897-34909Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar). Lee et al. (24Lee E.J. Hyun S.H. Chun J. Kang S.S. Biochem. Biophys. Res. Commun. 2007; 358: 783-788Crossref PubMed Scopus (10) Google Scholar) reported that Fe65 interacts with NEK6, down-regulates Thr210 phosphorylation, and induces apoptosis. However, kinases that can phosphorylate Thr210 have not been identified. Because the T210A mutant significantly decreased NEK6 activity, the identification of the upstream kinase is very important for the mechanistic study of NEK6 regulation. Interestingly, Thr210 is followed by a proline residue that can be recognized by Pin1. The interaction between NEK6 and Pin1 has been reported (9Chen J. Li L. Zhang Y. Yang H. Wei Y. Zhang L. Liu X. Yu L. Biochem. Biophys. Res. Commun. 2006; 341: 1059-1065Crossref PubMed Scopus (34) Google Scholar). Pin1 specifically recognizes a proline preceded by a phosphorylated serine or threonine residue (phospho-Ser/Thr-Pro motif) and catalyzes the cis-trans isomerization of the target peptidyl-prolyl bonds (14Wulf G. Finn G. Suizu F. Lu K.P. Nat. Cell Biol. 2005; 7: 435-441Crossref PubMed Scopus (216) Google Scholar). The importance of Ser206 and Thr210 for NEK6 activity was further explained by the homology model of NEK6. Ser206 and Thr210 seemed to be located at crucial sites for interacting with phosphoamino acid-binding proteins. These substrate recruitment sites are normally shaped by the conformation adopted by the activation loop upon phosphorylation. In contrast, Thr202 is on the edge of the pocket and thus does not seem to be part of the substrate binding surface. Therefore, the phosphorylation of Ser206 and Thr210 might possibly play an important role in the binding of substrates.In summary, these experiments demonstrate that ectopic expression of NEK6 induces anchorage-independent transformation of JB6 Cl41 mouse epidermal cells. Based on our findings, the most likely mechanism that can account for this biological effect involves, at least in part, the activation of STAT3 through its phosphorylation on Ser727. 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 may represent a novel chemotherapeutic target. IntroductionNEK6 (NIMA-related kinase 6) is a serine/threonine kinase identified as a homologue of the Aspergillus nidulans protein NIMA (never in mitosis, gene A). Aspergillus NIMA is essential for the initiation of mitosis, and its degradation is necessary for mitotic exit (1Osmani S.A. May G.S. Morris N.R. J. Cell Biol. 1987; 104: 1495-1504Crossref PubMed Scopus (228) Google Scholar, 2Pu R.T. Osmani S.A. EMBO J. 1995; 14: 995-1003Crossref PubMed Scopus (73) Google Scholar). The NEK6 protein level is also increased during mitosis, concomitant with an increase in NEK6 activity (3Belham C. Roig J. Caldwell J.A. Aoyama Y. Kemp B.E. Comb M. Avruch J. J. Biol. Chem. 2003; 278: 34897-34909Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar). Overexpression of catalytically inactive NEK6 causes arrest of cells in mitosis and interferes with chromosome segregation (4Yin M.J. Shao L. Voehringer D. Smeal T. Jallal B. J. Biol. Chem. 2003; 278: 52454-52460Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). Furthermore, depletion of the endogenous NEK6 protein using siRNA in HeLa cells resulted in mitotic arrest followed by apoptosis (4Yin M.J. Shao L. Voehringer D. Smeal T. Jallal B. J. Biol. Chem. 2003; 278: 52454-52460Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). Therefore, NEK6 activity appears to be required for proper anaphase progression with cells either arresting at the spindle checkpoint and undergoing apoptosis or completing mitosis but with the acquisition of nuclear abnormalities in the process. Inhibition of NEK6 has been suggested to be involved in G2/M phase cell cycle arrest induced by DNA damage (5Lee M.Y. Kim H.J. Kim M.A. Jee H.J. Kim A.J. Bae Y.S. Park J.I. Chung J.H. Yun J. Cell Cycle. 2008; 7: 2705-2709Crossref PubMed Scopus (42) Google Scholar).Despite the critical role of NEK6 in maintaining proper progression of the cell cycle, the physiological substrates of NEK6 are largely undefined. NEK6 was initially identified in a screen to determine upstream kinases of the 70 ribosomal S6 kinase (6Belham C. Comb M.J. Avruch J. Curr. Biol. 2001; 11: 1155-1167Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar). However, additional evidence did not support S6 kinase as a physiological substrate of NEK6 (7Lizcano J.M. Deak M. Morrice N. Kieloch A. Hastie C.J. Dong L. Schutkowski M. Reimer U. Alessi D.R. J. Biol. Chem. 2002; 277: 27839-27849Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar). NEK6 was suggested to phosphorylate the kinesin Eg5 at a novel site necessary for mitotic spindle formation (8Rapley J. Nicolàs M. Groen A. Regué L. Bertran M.T. Caelles C. Avruch J. Roig J. J. Cell Sci. 2008; 121: 3912-3921Crossref PubMed Scopus (97) Google Scholar).A possible role for NEK6 in tumorigenesis has been indicated. Analysis of hepatic cancer carcinomas showed that nek6 mRNA expression was up-regulated in 70% of all cancers examined and correlated well with the up-regulation of peptidyl-prolyl isomerase or Pin1 (9Chen J. Li L. Zhang Y. Yang H. Wei Y. Zhang L. Liu X. Yu L. Biochem. Biophys. Res. Commun. 2006; 341: 1059-1065Crossref PubMed Scopus (34) Google Scholar). Because Pin1 plays an important role in the regulation of cell cycle and is prevalently overexpressed in human cancers, it is regarded as a new potential therapeutic target. Furthermore, evidence indicates that the growth rate of MDA-MB-231 human breast cancer cells is reduced by the overexpression of catalytically inactive NEK6 (4Yin M.J. Shao L. Voehringer D. Smeal T. Jallal B. J. Biol. Chem. 2003; 278: 52454-52460Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). However, the biological functions and mechanisms of NEK6 activity in carcinogenesis are largely unknown. Thus, the identification of key substrates is probably the most important component in discovering the function of NEK6 in carcinogenesis.In the present study, we demonstrate that NEK6 is overexpressed in various human cancer tissues, and ectopic expression of NEK6 increases tumor promoter-induced transformation of JB6 Cl41 mouse epidermal cells. We also discovered that STAT3, a member of the signal transducers and activators of transcription (STAT) family, is a novel target of NEK6. STAT3, which was originally discovered as a mediator in the cytokine signaling pathway, plays an important role in carcinogenesis, including anchorage-independent transformation of JB6 Cl41 cells (10Yu C.Y. Wang L. Khaletskiy A. Farrar W.L. Larner A. Colburn N.H. Li J.J. Oncogene. 2002; 21: 3949-3960Crossref PubMed Scopus (34) Google Scholar). Taken together, these results provide strong evidence linking NEK6 to carcinogenesis." @default.
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• W2058004911 title "Role of NEK6 in Tumor Promoter-induced Transformation in JB6 C141 Mouse Skin Epidermal Cells" @default.
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