臺灣博碩士論文加值系統

細胞內訊息傳遞是細胞重要的生理作用，它引發細胞對外界刺激的反應。例如：細胞的生長、分裂、分化和凋亡，而這些細胞作用維繫著生物組織或器官結構和功能的恆定。在此訊息傳遞的網路中，蛋白激酶 (protein kinase) 所調控的蛋白質磷酸化作用扮演著重要的角色。根據過去的研究顯示，蛋白激酶的功能失調會造成正常生理作用的缺失與引發疾病的發生。例如：神經發育不全、腫瘤發生、和免疫反應病變。而從人體基因體圖譜預判，約有上千種蛋白激酶的存在，其中只有數百種蛋白激酶有相關的研究。在本論文中利用數位選殖(digital cloning)取得一新的 MST4蛋白激酶，依據其氨基酸序列比對發現 MST4與MST3蛋白激酶在激酶活性中心有88%的相似度。MST4蛋白激酶的訊息核醣核酸大量表現在胎盤、胸腺和周邊血球等組織，亦發現大量存在於大腸直腸與肝臟癌化組織中。而進一步發現MST4蛋白激酶主要存在於細胞質中，藉由組織切片染色亦發現MST4蛋白激酶大量存在癌化的大腸直腸組織。這些結果顯示，MST4激酶與癌症的發生可能有相關。同時，MST4蛋白激酶的蛋白質磷酸化作用活性可以激活ERK細胞素激活的蛋白激酶 (mitogen-activated protein kinase, MAPK) 相關的細胞內訊息傳遞路徑，而此激活作用不需經由 Ras或 Raf的參與，但會透過 MEK1的媒介。MST4蛋白激酶亦可以藉由激活ERK細胞素激活的蛋白激酶相關的細胞內訊息傳遞而導致細胞轉型作用，而MST4蛋白激酶所引起的細胞轉型可能與癌症發生的原因相關。依據最近的蛋白激酶分類，MST4蛋白激酶屬於 GCK蛋白激酶第三型。此型的蛋白激酶會受到許多細胞素 (例如:EGF、PDGF、TNFa、interleukins) 的激活而引發細胞內訊息傳遞促成細胞生理變化。MST4蛋白激酶表現型的細胞可以降低腫瘤壞死因子a型 (tumor necrosis factor a, TNFa)所引起的細胞凋亡。其作用機轉與TNFa所引發細胞內訊息傳遞有關，且TNFa可以激活 MST4蛋白激酶的活性。此外，MST4蛋白激酶會減弱TNFa引發的 JNK MAPK的細胞內訊息傳遞，也會激活 NF-kB (nuclear factor —kappa B)轉錄因子的活性，而這激活作用會因腫瘤壞死因子a型的刺激而更顯著。實驗結果亦進一步顯示，MST4蛋白激酶引發的NF-kB轉錄因子的活化，是經由 IKKa、IKKb、和 IkBa的媒介，在TNFa刺激時亦相同。而 MST4蛋白激酶對 TNFa誘發性的細胞凋亡的減弱作用，是與激活ERK MAPK細胞內訊息傳遞和 NF-kB轉錄因子的活化有關。綜觀之， MST4蛋白激酶 (1)會藉由調節 ERK MAPK細胞內訊息傳遞引發細胞轉型作用；(3)會減弱TNFa誘發性的 JNK MAPK細胞內訊息傳遞；(4)會激活IKKs引起 IkBa 減少致使NF-kB轉錄因子的活化；(5) 對TNFa誘發性的細胞凋亡的減弱作用會受ERK MAPK細胞內訊息傳遞的阻斷和 NF-kB轉錄因子的活性減弱而消失。因此，MST4蛋白激酶透過上述諸多可能的作用機制去調控生物的活性，並初步發現MST4蛋白激酶與腫瘤形成或其它相關疾病有密切關聯。而為進一步釐清MST4蛋白激酶在正常細胞或病變細胞中的作用機制，進行更多的MST4蛋白激酶相關的實驗是刻不容緩。

During the past two decades, protein kinases have taken the center stage in the field of signal transduction initiated by cells perceiving of extracellular perturbation and control many cellular processes include cell growth, proliferation, differentiation, and apoptosis. However, the kinase signal networks have been increasingly constructed for understanding the most cellular responses by discovering more novel kinases. We used the digital-cloning method to dig out several novel kinases related to tyrosine or serine/threonine kinases. One of the novel serine/threonine kinase has been designated as MST4 (accession number AF231012) shared the highly conserved kinase catalytic domain with MST3 and SOK. MST4 has also been classified in the GCK subfamily III and MST4 transcripts highly expressed in normal adult placenta, thymus, peripheral blood leukocytes, colorectal carcinoma, and hepatoma tissues, expressed at a low level in normal colon tissue, and were not detectable in adult liver. Endogenous and ectopically expressed MST4 were mainly detected in the cytoplasm and colorectal carcinoma tissues. These finding implied that MST4 kinase sould be a tissue-specific kinase and potently related to cancer disease. Further, MST4 displays the enzymatic activity in the in vitro kinase assay and activates ERK cascade in a MEK1-dependent, but Ras/Raf-independent manner. Importantly, the overexpressed MST4 potentiates cell transformation capacity in an anchorage-independent growth (AIG) assay in MEK1-dependent manner. These evidences suggested that the MST4-MEK1-ERK pathway could be the possible mechanism in the MST4 related pathological revealings. In addition, we have also explored another function of MST4 in cell apoptosis. The TNFa-induced cell apoptosis can be attenuated by the overexpressed MST4. Analysis of TNF-a induced signaling pathways revealed that MST4 is capable of activating NF-kB transactivation as well as decreasing JNK activation. The activation of NF-kB by MST4 can be blocked by the dominant negative mutant of IkBa, IKKa, or IKKb, suggesting that MST4 activates NF-kB through IKK-IkBa pathway. Take together, MST4 exerts two major functions in TNFa downstream signaling; it attenuates JNK activation and bridges the cross talk between MAPK cascade and NFkB transactivation in TNFa-dependent or —independent manner. Further, MST4 attenuates the TNFa-induced apoptosis and the attenuation could be abolished by SN50 (NF-kB inhibitor) or PD98059 (MEK1 inhibitor). Summarily, we have first shown that MST4 kinase decreased TNFa-mediated JNK cascade activation and NF-kB transactivation by IKKa, IKKb, IkBa, and MEK1 in TNFa-dependent manners. MST4 could modulate important cellular processes included cellular transformation and apoptosis. However, MST4 has been suggested to serve as the important candidate role in the tumorogenesis or other pathological revelations. Perspectively, the advanced approaches of MST4 characterization should be urgently carried out for exploring the biological significances of MST4.

Contents
List of Figure……………………………………………………………………..…III
List of abbreviation…………………………………………………………………IV
Chinese Summary…………………………………………………………………..VI
English Summary……………………………………………………………….VIII
Chapter I: General introduction……………………………………………….……1
Chapter II: MST4, a new Ste20-related kinase that mediates cell growth and
transformation via modulating ERK pathway……………………..20
Abstract………………………………………………………………...21
Introduction……………………………………………………………22
Materials and Methods………………………………………………..25
Results……………………………………………………………….…32
Discussion………………………………………………………………38
Chapter III: MST4 kinase attenuates TNFa-induced apoptosis via modulating
NF-kB transactivation………………………………………………55
Abstract………………………………………………………………...56
Introduction……………………………………………………………57
Materials and Methods………………………………………………..62
Results………………………………………………………………….67
Discussion………………………………………………………………71
Chapter IV: Summary and discussion………………………………………..……86
References………………………………………………………….…..89

1. 2001. HUGO urges genetic benefit-sharing. Community Genet 3:88-92.
2. Aggarwal, B. B. 2000. Tumour necrosis factors receptor associated signalling molecules and their role in activation of apoptosis, JNK and NF-kappaB. Ann Rheum Dis 59 Suppl 1:i6-16.
3. Aikawa, Y., M. Yamamoto, T. Yamamoto, K. Morimoto, and K. Tanaka. 2002. An anti-rheumatic agent T-614 inhibits NF-kappaB activation in LPS- and TNF-alpha-stimulated THP-1 cells without interfering with IkappaBalpha degradation. Inflamm Res 51:188-94.
4. Antonelli, A., R. Crinelli, M. Bianchi, A. Cerasi, L. Gentilini, G. Serafini, and M. Magnani. 1999. Efficient inhibition of macrophage TNF-alpha production upon targeted delivery of K48R ubiquitin. Br J Haematol 104:475-81.
5. Aota, K., M. Azuma, T. Tamatani, T. Yamashita, Y. Ashida, and M. Sato. 2002. Stable inhibition of NF-kappa B in salivary gland cells does not enhance sensitivity to TNF-alpha-induced apoptosis due to upregulation of TRAF-1 expression. Exp Cell Res 276:111-9.
6. Arnold, R., J. Liou, H. C. Drexler, A. Weiss, and F. Kiefer. 2001. Caspase-mediated cleavage of hematopoietic progenitor kinase 1 (HPK1) converts an activator of NFkappaB into an inhibitor of NFkappaB. J Biol Chem 276:14675-84.
7. Baker, S. J., and E. P. Reddy. 1998. Modulation of life and death by the TNF receptor superfamily. Oncogene 17:3261-70.
8. Basu, S., and R. Kolesnick. 1998. Stress signals for apoptosis: ceramide and c-Jun kinase. Oncogene 17:3277-85.
9. Becker, E., U. Huynh-Do, S. Holland, T. Pawson, T. O. Daniel, and E. Y. Skolnik. 2000. Nck-interacting Ste20 kinase couples Eph receptors to c-Jun N-terminal kinase and integrin activation. Mol Cell Biol 20:1537-45.
10. Blanco-Molina, M., G. C. Tron, A. Macho, C. Lucena, M. A. Calzado, E. Munoz, and G. Appendino. 2001. Ingenol esters induce apoptosis in Jurkat cells through an AP-1 and NF-kappaB independent pathway. Chem Biol 8:767-78.
11. Blattner, C., E. Tobiasch, M. Litfen, H. J. Rahmsdorf, and P. Herrlich. 1999. DNA damage induced p53 stabilization: no indication for an involvement of p53 phosphorylation. Oncogene 18:1723-32.
12. Brivanlou, A. H., and J. E. Darnell, Jr. 2002. Signal transduction and the control of gene expression. Science 295:813-8.
13. Brown, J. L., L. Stowers, M. Baer, J. Trejo, S. Coughlin, and J. Chant. 1996. Human Ste20 homologue hPAK1 links GTPases to the JNK MAP kinase pathway. Curr Biol 6:598-605.
14. Brown, K. D., B. S. Hostager, and G. A. Bishop. 2002. Regulation of TRAF2 Signaling by Self-induced Degradation. J Biol Chem 277:19433-8.
15. Cao, Q., K. M. Mak, and C. S. Lieber. 2002. Dilinoleoylphosphatidylcholine decreases LPS-induced TNF-alpha generation in Kupffer cells of ethanol-fed rats: respective roles of MAPKs and NF-kappaB. Biochem Biophys Res Commun 294:849-53.
16. Cardier, J. E., and C. L. Erickson-Miller. 2002. Fas (CD95)- and tumor necrosis factor-mediated apoptosis in liver endothelial cells: role of caspase-3 and the p38 MAPK. Microvasc Res 63:10-8.
17. Cau, J., S. Faure, S. Vigneron, J. C. Labbe, C. Delsert, and N. Morin. 2000. Regulation of Xenopus p21-activated kinase (X-PAK2) by Cdc42 and maturation-promoting factor controls Xenopus oocyte maturation. J Biol Chem 275:2367-75.
18. Chadee, D. N., T. Yuasa, and J. M. Kyriakis. 2002. Direct activation of mitogen-activated protein kinase kinase kinase MEKK1 by the Ste20p homologue GCK and the adapter protein TRAF2. Mol Cell Biol 22:737-49.
19. Chainy, G. B., S. K. Manna, M. M. Chaturvedi, and B. B. Aggarwal. 2000. Anethole blocks both early and late cellular responses transduced by tumor necrosis factor: effect on NF-kappaB, AP-1, JNK, MAPKK and apoptosis. Oncogene 19:2943-50.
20. Chan, E. D., and D. W. Riches. 1998. Potential role of the JNK/SAPK signal transduction pathway in the induction of iNOS by TNF-alpha. Biochem Biophys Res Commun 253:790-6.
21. Chan, W. H., and J. S. Yu. 2000. Inhibition of UV irradiation-induced oxidative stress and apoptotic biochemical changes in human epidermal carcinoma A431 cells by genistein. J Cell Biochem 78:73-84.
22. Chan, W. H., J. S. Yu, and S. D. Yang. 1998. Heat shock stress induces cleavage and activation of PAK2 in apoptotic cells. J Protein Chem 17:485-94.
23. Chan, W. H., J. S. Yu, and S. D. Yang. 1999. PAK2 is cleaved and activated during hyperosmotic shock-induced apoptosis via a caspase-dependent mechanism: evidence for the involvement of oxidative stress. J Cell Physiol 178:397-408.
24. Chaturvedi, V., J. Z. Qin, M. F. Denning, D. Choubey, M. O. Diaz, and B. J. Nickoloff. 2001. Abnormal NF-kappaB signaling pathway with enhanced susceptibility to apoptosis in immortalized keratinocytes. J Dermatol Sci 26:67-78.
25. Chen, A., and B. H. Davis. 1999. UV irradiation activates JNK and increases alphaI(I) collagen gene expression in rat hepatic stellate cells. J Biol Chem 274:158-64.
26. Chen, H. C., H. J. Kung, and D. Robinson. 1998. Digital cloning: identification of human cDNAs homologous to novel kinases through expressed sequence tag database searching. J Biomed Sci 5:86-92.
27. Chen, S., and D. G. Gardner. 2002. Osmoregulation of natriuretic peptide receptor signaling in inner medullary collecting duct. A requirement for p38 MAPK. J Biol Chem 277:6037-43.
28. Chen, Y. R., C. F. Meyer, B. Ahmed, Z. Yao, and T. H. Tan. 1999. Caspase-mediated cleavage and functional changes of hematopoietic progenitor kinase 1 (HPK1). Oncogene 18:7370-7.
29. Chen, Z., M. Hutchison, and M. H. Cobb. 1999. Isolation of the protein kinase TAO2 and identification of its mitogen-activated protein kinase/extracellular signal-regulated kinase kinase binding domain. J Biol Chem 274:28803-7.
30. Cherkasova, V., D. M. Lyons, and E. A. Elion. 1999. Fus3p and Kss1p control G1 arrest in Saccharomyces cerevisiae through a balance of distinct arrest and proliferative functions that operate in parallel with Far1p. Genetics 151:989-1004.
31. Cohen, O., and A. Kimchi. 2001. DAP-kinase: from functional gene cloning to establishment of its role in apoptosis and cancer. Cell Death Differ 8:6-15.
32. Coles, L. C., and P. E. Shaw. 2002. PAK1 primes MEK1 for phosphorylation by Raf-1 kinase during cross-cascade activation of the ERK pathway. Oncogene 21:2236-44.
33. Coppolino, M. G., M. Krause, P. Hagendorff, D. A. Monner, W. Trimble, S. Grinstein, J. Wehland, and A. S. Sechi. 2001. Evidence for a molecular complex consisting of Fyb/SLAP, SLP-76, Nck, VASP and WASP that links the actin cytoskeleton to Fcgamma receptor signalling during phagocytosis. J Cell Sci 114:4307-18.
34. Cullen, P. J., J. Schultz, J. Horecka, B. J. Stevenson, Y. Jigami, and G. F. Sprague, Jr. 2000. Defects in protein glycosylation cause SHO1-dependent activation of a STE12 signaling pathway in yeast. Genetics 155:1005-18.
35. Dan, I., S. E. Ong, N. M. Watanabe, B. Blagoev, M. M. Nielsen, E. Kajikawa, T. Z. Kristiansen, M. Mann, and A. Pandey. 2002. Cloning of MASK, a novel member of the mammalian germinal center kinase III subfamily, with apoptosis-inducing properties. J Biol Chem 277:5929-39.
36. Dan, I., N. M. Watanabe, and A. Kusumi. 2001. The Ste20 group kinases as regulators of MAP kinase cascades. Trends Cell Biol 11:220-30.
37. De Souza, P. M., H. Kankaanranta, A. Michael, P. J. Barnes, M. A. Giembycz, and M. A. Lindsay. 2002. Caspase-catalyzed cleavage and activation of Mst1 correlates with eosinophil but not neutrophil apoptosis. Blood 99:3432-8.
38. Delude, R. L., A. Yoshimura, R. R. Ingalls, and D. T. Golenbock. 1998. Construction of a lipopolysaccharide reporter cell line and its use in identifying mutants defective in endotoxin, but not TNF-alpha, signal transduction. J Immunol 161:3001-9.
39. Diener, K., X. S. Wang, C. Chen, C. F. Meyer, G. Keesler, M. Zukowski, T. H. Tan, and Z. Yao. 1997. Activation of the c-Jun N-terminal kinase pathway by a novel protein kinase related to human germinal center kinase. Proc Natl Acad Sci U S A 94:9687-92.
40. Eichinger, L., M. Bahler, M. Dietz, C. Eckerskorn, and M. Schleicher. 1998. Characterization and cloning of a Dictyostelium Ste20-like protein kinase that phosphorylates the actin-binding protein severin. J Biol Chem 273:12952-9.
41. Ellinger-Ziegelbauer, H., H. Karasuyama, E. Yamada, K. Tsujikawa, K. Todokoro, and E. Nishida. 2000. Ste20-like kinase (SLK), a regulatory kinase for polo-like kinase (Plk) during the G2/M transition in somatic cells. Genes Cells 5:491-8.
42. Endo, J., N. Toyama-Sorimachi, C. Taya, S. Kuramochi-Miyagawa, K. Nagata, K. Kuida, T. Takashi, H. Yonekawa, Y. Yoshizawa, N. Miyasaka, and H. Karasuyama. 2000. Deficiency of a STE20/PAK family kinase LOK leads to the acceleration of LFA-1 clustering and cell adhesion of activated lymphocytes. FEBS Lett 468:234-8.
43. Fan, S., Y. X. Ma, M. Gao, R. Q. Yuan, Q. Meng, I. D. Goldberg, and E. M. Rosen. 2001. The multisubstrate adapter Gab1 regulates hepatocyte growth factor (scatter factor)-c-Met signaling for cell survival and DNA repair. Mol Cell Biol 21:4968-84.
44. Faure, S., S. Vigneron, M. Doree, and N. Morin. 1997. A member of the Ste20/PAK family of protein kinases is involved in both arrest of Xenopus oocytes at G2/prophase of the first meiotic cell cycle and in prevention of apoptosis. Embo J 16:5550-61.
45. Feng, Y., L. Y. Song, E. Kincaid, S. K. Mahanty, and E. A. Elion. 1998. Functional binding between Gbeta and the LIM domain of Ste5 is required to activate the MEKK Ste11. Curr Biol 8:267-78.
46. Ferlito, M., O. G. Romanenko, S. Ashton, F. Squadrito, P. V. Halushka, and J. A. Cook. 2001. Effect of cross-tolerance between endotoxin and TNF-alpha or IL-1beta on cellular signaling and mediator production. J Leukoc Biol 70:821-9.
47. Fernandez, P. C., J. Machado, Jr., V. T. Heussler, C. Botteron, G. H. Palmer, and D. A. Dobbelaere. 1999. The inhibition of NF-kappaB activation pathways and the induction of apoptosis by dithiocarbamates in T cells are blocked by the glutathione precursor N-acetyl-L-cysteine. Biol Chem 380:1383-94.
48. Fotin-Mleczek, M., F. Henkler, D. Samel, M. Reichwein, A. Hausser, I. Parmryd, P. Scheurich, J. A. Schmid, and H. Wajant. 2002. Apoptotic crosstalk of TNF receptors: TNF-R2-induces depletion of TRAF2 and IAP proteins and accelerates TNF-R1-dependent activation of caspase-8. J Cell Sci 115:2757-2770.
49. Frost, J. A., S. Xu, M. R. Hutchison, S. Marcus, and M. H. Cobb. 1996. Actions of Rho family small G proteins and p21-activated protein kinases on mitogen-activated protein kinase family members. Mol Cell Biol 16:3707-13.
50. Fu, C. A., M. Shen, B. C. Huang, J. Lasaga, D. G. Payan, and Y. Luo. 1999. TNIK, a novel member of the germinal center kinase family that activates the c-Jun N-terminal kinase pathway and regulates the cytoskeleton. J Biol Chem 274:30729-37.
51. Gabai, V. L., K. Mabuchi, D. D. Mosser, and M. Y. Sherman. 2002. Hsp72 and stress kinase c-jun N-terminal kinase regulate the bid-dependent pathway in tumor necrosis factor-induced apoptosis. Mol Cell Biol 22:3415-24.
52. Gilbreth, M., P. Yang, D. Wang, J. Frost, A. Polverino, M. H. Cobb, and S. Marcus. 1996. The highly conserved skb1 gene encodes a protein that interacts with Shk1, a fission yeast Ste20/PAK homolog. Proc Natl Acad Sci U S A 93:13802-7.
53. Graves, J. D., K. E. Draves, Y. Gotoh, E. G. Krebs, and E. A. Clark. 2001. Both phosphorylation and caspase-mediated cleavage contribute to regulation of the Ste20-like protein kinase Mst1 during CD95/Fas-induced apoptosis. J Biol Chem 276:14909-15.
54. Graves, J. D., Y. Gotoh, K. E. Draves, D. Ambrose, D. K. Han, M. Wright, J. Chernoff, E. A. Clark, and E. G. Krebs. 1998. Caspase-mediated activation and induction of apoptosis by the mammalian Ste20-like kinase Mst1. Embo J 17:2224-34.
55. Greulich, H., and R. L. Erikson. 1998. An analysis of Mek1 signaling in cell proliferation and transformation. J Biol Chem 273:13280-8.
56. Guiet, C., E. Silvestri, E. De Smaele, G. Franzoso, and P. Vito. 2002. c-FLIP efficiently rescues TRAF-2-/- cells from TNF-induced apoptosis. Cell Death Differ 9:138-44.
57. Guo, M., E. Sato, X. Li, E. Mori, S. Saito, and T. Mori. 2002. Induction of apoptosis mediated by fas receptor and activation of caspase-3 in MRL-+/+ or MRL-lpr/lpr murine oocytes. Zygote 10:17-22.
58. Hanks, S. K., and R. A. Lindberg. 1991. Use of degenerate oligonucleotide probes to identify clones that encode protein kinases. Methods Enzymol 200:525-32.
59. Hanks, S. K., and A. M. Quinn. 1991. Protein kinase catalytic domain sequence database: identification of conserved features of primary structure and classification of family members. Methods Enzymol 200:38-62.
60. Harden, N., J. Lee, H. Y. Loh, Y. M. Ong, I. Tan, T. Leung, E. Manser, and L. Lim. 1996. A Drosophila homolog of the Rac- and Cdc42-activated serine/threonine kinase PAK is a potential focal adhesion and focal complex protein that colocalizes with dynamic actin structures. Mol Cell Biol 16:1896-908.
61. Hartkamp, J., J. Troppmair, and U. R. Rapp. 1999. The JNK/SAPK activator mixed lineage kinase 3 (MLK3) transforms NIH 3T3 cells in a MEK-dependent fashion. Cancer Res 59:2195-202.
62. Hashimoto, S., A. Tsubouchi, Y. Mazaki, and H. Sabe. 2001. Interaction of paxillin with p21-activated Kinase (PAK). Association of paxillin alpha with the kinase-inactive and the Cdc42-activated forms of PAK3. J Biol Chem 276:6037-45.
63. Hayakawa, A., J. Wu, Y. Kawamoto, Y. W. Zhou, S. Tanuma, I. Nakashima, and H. Suzuki. 2002. Activation of caspase-8 is critical for sensitivity to cytotoxic anti-Fas antibody-induced apoptosis in human ovarian cancer cells. Apoptosis 7:107-13.
64. Herr, I., D. Wilhelm, T. Bohler, P. Angel, and K. M. Debatin. 1999. JNK/SAPK activity is not sufficient for anticancer therapy-induced apoptosis involving CD95-L, TRAIL and TNF-alpha. Int J Cancer 80:417-24.
65. Heyninck, K., and R. Beyaert. 2001. Crosstalk between NF-kappaB-activating and apoptosis-inducing proteins of the TNF-receptor complex. Mol Cell Biol Res Commun 4:259-65.
66. Hirose, T., W. Fujimoto, T. Tamaai, K. H. Kim, H. Matsuura, and A. M. Jetten. 1994. TAK1: molecular cloning and characterization of a new member of the nuclear receptor superfamily. Mol Endocrinol 8:1667-80.
67. Hochedlinger, K., E. F. Wagner, and K. Sabapathy. 2002. Differential effects of JNK1 and JNK2 on signal specific induction of apoptosis. Oncogene 21:2441-5.
68. Hu, M. C., W. R. Qiu, X. Wang, C. F. Meyer, and T. H. Tan. 1996. Human HPK1, a novel human hematopoietic progenitor kinase that activates the JNK/SAPK kinase cascade. Genes Dev 10:2251-64.
69. Hu, M. C., Y. Wang, W. R. Qiu, A. Mikhail, C. F. Meyer, and T. H. Tan. 1999. Hematopoietic progenitor kinase-1 (HPK1) stress response signaling pathway activates IkappaB kinases (IKK-alpha/beta) and IKK-beta is a developmentally regulated protein kinase. Oncogene 18:5514-24.
70. Hutchison, M., K. S. Berman, and M. H. Cobb. 1998. Isolation of TAO1, a protein kinase that activates MEKs in stress-activated protein kinase cascades. J Biol Chem 273:28625-32.
71. Ibe, W., W. Bartels, S. Lindemann, T. Grosser, M. Buerke, J. P. Boissel, J. Meyer, and H. Darius. 2001. Involvement of PKC and NF-kappaB in nitric oxide induced apoptosis in human coronary artery smooth muscle cells. Cell Physiol Biochem 11:231-40.
72. Inamura, N., Y. Enokido, and H. Hatanaka. 2001. Involvement of c-Jun N-terminal kinase and caspase 3-like protease in DNA damage-induced, p53-mediated apoptosis of cultured mouse cerebellar granule neurons. Brain Res 904:270-8.
73. Ishitani, T., J. Ninomiya-Tsuji, S. Nagai, M. Nishita, M. Meneghini, N. Barker, M. Waterman, B. Bowerman, H. Clevers, H. Shibuya, and K. Matsumoto. 1999. The TAK1-NLK-MAPK-related pathway antagonizes signalling between beta-catenin and transcription factor TCF. Nature 399:798-802.
74. Jaffer, Z. M., and J. Chernoff. 2002. p21-Activated kinases: three more join the Pak. Int J Biochem Cell Biol 34:713-7.
75. Johnston, A. M., G. Naselli, L. J. Gonez, R. M. Martin, L. C. Harrison, and H. J. DeAizpurua. 2000. SPAK, a STE20/SPS1-related kinase that activates the p38 pathway. Oncogene 19:4290-7.
76. Juliano, R. L. 2002. Signal transduction by cell adhesion receptors and the cytoskeleton: functions of integrins, cadherins, selectins, and immunoglobulin-superfamily members. Annu Rev Pharmacol Toxicol 42:283-323.
77. Kakeya, H., R. Onose, and H. Osada. 1998. Caspase-mediated activation of a 36-kDa myelin basic protein kinase during anticancer drug-induced apoptosis. Cancer Res 58:4888-94.
78. Kayali, A. G., D. A. Austin, and N. J. Webster. 2000. Stimulation of MAPK cascades by insulin and osmotic shock: lack of an involvement of p38 mitogen-activated protein kinase in glucose transport in 3T3-L1 adipocytes. Diabetes 49:1783-93.
79. Kelliher, M. A., S. Grimm, Y. Ishida, F. Kuo, B. Z. Stanger, and P. Leder. 1998. The death domain kinase RIP mediates the TNF-induced NF-kappaB signal. Immunity 8:297-303.
80. Kiefer, F., L. A. Tibbles, M. Anafi, A. Janssen, B. W. Zanke, N. Lassam, T. Pawson, J. R. Woodgett, and N. N. Iscove. 1996. HPK1, a hematopoietic protein kinase activating the SAPK/JNK pathway. Embo J 15:7013-25.
81. Kim, H. J., and K. J. Lee. 2002. Heat shock and ceramide have different apoptotic pathways in radiation induced fibrosarcoma (RIF) cells. Mol Cell Biochem 229:139-51.
82. Kim, K. W., B. J. Kim, C. W. Chung, D. G. Jo, I. K. Kim, Y. H. Song, Y. K. Kwon, H. N. Woo, and Y. K. Jung. 2002. Caspase cleavage product lacking amino-terminus of IkappaBalpha sensitizes resistant cells to TNF-alpha and TRAIL-induced apoptosis. J Cell Biochem 85:334-45.
83. Kyriakis, J. M., and J. Avruch. 1996. Protein kinase cascades activated by stress and inflammatory cytokines. Bioessays 18:567-77.
84. Leberer, E., D. Dignard, D. Harcus, D. Y. Thomas, and M. Whiteway. 1992. The protein kinase homologue Ste20p is required to link the yeast pheromone response G-protein beta gamma subunits to downstream signalling components. Embo J 11:4815-24.
85. Leberer, E., D. Harcus, I. D. Broadbent, K. L. Clark, D. Dignard, K. Ziegelbauer, A. Schmidt, N. A. Gow, A. J. Brown, and D. Y. Thomas. 1996. Signal transduction through homologs of the Ste20p and Ste7p protein kinases can trigger hyphal formation in the pathogenic fungus Candida albicans. Proc Natl Acad Sci U S A 93:13217-22.
86. Lee, K. K., M. Murakawa, E. Nishida, S. Tsubuki, S. Kawashima, K. Sakamaki, and S. Yonehara. 1998. Proteolytic activation of MST/Krs, STE20-related protein kinase, by caspase during apoptosis. Oncogene 16:3029-37.
87. Lee, K. K., T. Ohyama, N. Yajima, S. Tsubuki, and S. Yonehara. 2001. MST, a physiological caspase substrate, highly sensitizes apoptosis both upstream and downstream of caspase activation. J Biol Chem 276:19276-85.
88. Li, W., C. D. Whaley, J. L. Bonnevier, A. Mondino, M. E. Martin, K. M. Aagaard-Tillery, and D. L. Mueller. 2001. CD28 signaling augments Elk-1-dependent transcription at the c-fos gene during antigen stimulation. J Immunol 167:827-35.
89. Li, X., Y. Yang, and J. D. Ashwell. 2002. TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2. Nature 416:345-7.
90. Lin, J. L., H. C. Chen, H. I. Fang, D. Robinson, H. J. Kung, and H. M. Shih. 2001. MST4, a new Ste20-related kinase that mediates cell growth and transformation via modulating ERK pathway. Oncogene 20:6559-69.
91. Ling, P., C. F. Meyer, L. P. Redmond, J. W. Shui, B. Davis, R. R. Rich, M. C. Hu, R. L. Wange, and T. H. Tan. 2001. Involvement of hematopoietic progenitor kinase 1 in T cell receptor signaling. J Biol Chem 276:18908-14.
92. Lu, W., S. Katz, R. Gupta, and B. J. Mayer. 1997. Activation of Pak by membrane localization mediated by an SH3 domain from the adaptor protein Nck. Curr Biol 7:85-94.
93. Lynch, A. M., and M. A. Lynch. 2002. The age-related increase in IL-1 type I receptor in rat hippocampus is coupled with an increase in caspase-3 activation. Eur J Neurosci 15:1779-88.
94. Maccioni, R. B., J. P. Munoz, and L. Barbeito. 2001. The molecular bases of Alzheimer's disease and other neurodegenerative disorders. Arch Med Res 32:367-81.
95. Malinin, N. L., M. P. Boldin, A. V. Kovalenko, and D. Wallach. 1997. MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1. Nature 385:540-4.
96. Marinari, B., A. Costanzo, A. Viola, F. Michel, G. Mangino, O. Acuto, M. Levrero, E. Piccolella, and L. Tuosto. 2002. Vav cooperates with CD28 to induce NF-kappaB activation via a pathway involving Rac-1 and mitogen-activated kinase kinase 1. Eur J Immunol 32:447-56.
97. Martin, G. A., G. Bollag, F. McCormick, and A. Abo. 1995. A novel serine kinase activated by rac1/CDC42Hs-dependent autophosphorylation is related to PAK65 and STE20. Embo J 14:4385.
98. Meeker, R., and A. Fernandes. 2000. Osmotic and glutamate receptor regulation of c-Jun NH(2)-terminal protein kinase in neuroendocrine cells. Am J Physiol Endocrinol Metab 279:E475-86.
99. Mitsiades, C. S., and M. Koutsilieris. 2001. Molecular biology and cellular physiology of refractoriness to androgen ablation therapy in advanced prostate cancer. Expert Opin Investig Drugs 10:1099-115.
100. Mitsutake, N., H. Namba, S. S. Shklyaev, T. Tsukazaki, A. Ohtsuru, M. Ohba, T. Kuroki, H. Ayabe, and S. Yamashita. 2001. PKC delta mediates ionizing radiation-induced activation of c-Jun NH(2)-terminal kinase through MKK7 in human thyroid cells. Oncogene 20:989-96.
101. Mizuno, T., Y. Goto, K. Baba, K. Masuda, K. Ohno, and H. Tsujimoto. 2001. TNF-alpha-induced cell death in feline immunodeficiency virus-infected cells is mediated by the caspase cascade. Virology 287:446-55.
102. Mohan, R. R., W. J. Kim, and S. E. Wilson. 2000. Modulation of TNF-alpha-induced apoptosis in corneal fibroblasts by transcription factor NF-kappaB. Invest Ophthalmol Vis Sci 41:1327-36.
103. Moore, T. M., R. Garg, C. Johnson, M. J. Coptcoat, A. J. Ridley, and J. D. Morris. 2000. PSK, a novel STE20-like kinase derived from prostatic carcinoma that activates the c-Jun N-terminal kinase mitogen-activated protein kinase pathway and regulates actin cytoskeletal organization. J Biol Chem 275:4311-22.
104. Mosch, H. U., R. L. Roberts, and G. R. Fink. 1996. Ras2 signals via the Cdc42/Ste20/mitogen-activated protein kinase module to induce filamentous growth in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 93:5352-6.
105. Mukai, H., M. Miyahara, H. Takanaga, M. Kitagawa, H. Shibata, M. Shimakawa, and Y. Ono. 1995. Identification of Schizosaccharomyces pombe gene psk1+, encoding a novel putative serine/threonine protein kinase, whose mutation conferred resistance to phenylarsine oxide. Gene 166:155-9.
106. Nabeshima, S., Y. Hotta, and M. Okanishi. 1984. Construction of plasmid vectors from Streptomyces kasugaensis plasmids, pSK1 and pSK2. J Antibiot (Tokyo) 37:1026-37.
107. Nakano, K., J. Yamauchi, K. Nakagawa, H. Itoh, and N. Kitamura. 2000. NESK, a member of the germinal center kinase family that activates the c-Jun N-terminal kinase pathway and is expressed during the late stages of embryogenesis. J Biol Chem 275:20533-9.
108. Oehrl, W., C. Kardinal, S. Ruf, K. Adermann, J. Groffen, G. S. Feng, J. Blenis, T. H. Tan, and S. M. Feller. 1998. The germinal center kinase (GCK)-related protein kinases HPK1 and KHS are candidates for highly selective signal transducers of Crk family adapter proteins. Oncogene 17:1893-901.
109. Ori, N., Y. Eshed, P. Pinto, I. Paran, D. Zamir, and R. Fluhr. 1997. TAO1, a representative of the molybdenum cofactor containing hydroxylases from tomato. J Biol Chem 272:1019-25.
110. Osada, S., M. Izawa, T. Koyama, S. Hirai, and S. Ohno. 1997. A domain containing the Cdc42/Rac interactive binding (CRIB) region of p65PAK inhibits transcriptional activation and cell transformation mediated by the Ras-Rac pathway. FEBS Lett 404:227-33.
111. O'Sullivan, E., C. Kinnon, and P. Brickell. 1999. Wiskott-Aldrich syndrome protein, WASP. Int J Biochem Cell Biol 31:383-7.
112. Park, J. S., L. Qiao, Z. Z. Su, D. Hinman, K. Willoughby, R. McKinstry, A. Yacoub, G. J. Duigou, C. S. Young, S. Grant, M. P. Hagan, E. Ellis, P. B. Fisher, and P. Dent. 2001. Ionizing radiation modulates vascular endothelial growth factor (VEGF) expression through multiple mitogen activated protein kinase dependent pathways. Oncogene 20:3266-80.
113. Parnas, D., A. P. Haghighi, R. D. Fetter, S. W. Kim, and C. S. Goodman. 2001. Regulation of postsynaptic structure and protein localization by the Rho-type guanine nucleotide exchange factor dPix. Neuron 32:415-24.
114. Plumpe, J., N. P. Malek, C. T. Bock, T. Rakemann, M. P. Manns, and C. Trautwein. 2000. NF-kappaB determines between apoptosis and proliferation in hepatocytes during liver regeneration. Am J Physiol Gastrointest Liver Physiol 278:G173-83.
115. Pohlers, D., C. B. Schmidt-Weber, A. Franch, J. Kuhlmann, R. Brauer, F. Emmrich, and R. W. Kinne. 2002. Differential clinical efficacy of anti-CD4 monoclonal antibodies in rat adjuvant arthritis is paralleled by differential influence on NF-kappaB binding activity and TNF-alpha secretion of T cells. Arthritis Res 4:184-9.
116. Poinat, P., A. De Arcangelis, S. Sookhareea, X. Zhu, E. M. Hedgecock, M. Labouesse, and E. Georges-Labouesse. 2002. A Conserved Interaction between beta1 Integrin/PAT-3 and Nck-Interacting Kinase/MIG-15 that Mediates Commissural Axon Navigation in C. elegans. Curr Biol 12:622-31.
117. Pombo, C. M., J. V. Bonventre, A. Molnar, J. Kyriakis, and T. Force. 1996. Activation of a human Ste20-like kinase by oxidant stress defines a novel stress response pathway. Embo J 15:4537-46.
118. Pombo, C. M., T. Tsujita, J. M. Kyriakis, J. V. Bonventre, and T. Force. 1997. Activation of the Ste20-like oxidant stress response kinase-1 during the initial stages of chemical anoxia-induced necrotic cell death. Requirement for dual inputs of oxidant stress and increased cytosolic [Ca2+]. J Biol Chem 272:29372-9.
119. Pruitt, K., W. M. Pruitt, G. K. Bilter, J. K. Westwick, and C. J. Der. 2002. Raf-independent deregulation of p38 and JNK kinases are critical for Ras transformation. J Biol Chem.
120. Raghuram, V., K. R. Hallows, and J. K. Foskett. 2002. Yeast two-hybrid identification and analysis of protein interactions with CFTR. Methods Mol Med 70:365-81.
121. Raitt, D. C., F. Posas, and H. Saito. 2000. Yeast Cdc42 GTPase and Ste20 PAK-like kinase regulate Sho1-dependent activation of the Hog1 MAPK pathway. Embo J 19:4623-31.
122. Ramer, S. W., and R. W. Davis. 1993. A dominant truncation allele identifies a gene, STE20, that encodes a putative protein kinase necessary for mating in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 90:452-6.
123. Rhodes, N., L. Connell, and B. Errede. 1990. STE11 is a protein kinase required for cell-type-specific transcription and signal transduction in yeast. Genes Dev 4:1862-74.
124. Rimerman, R. A., A. Gellert-Randleman, and J. A. Diehl. 2000. Wnt1 and MEK1 cooperate to promote cyclin D1 accumulation and cellular transformation. J Biol Chem 275:14736-42.
125. Roig, J., and J. A. Traugh. 1999. p21-activated protein kinase gamma-PAK is activated by ionizing radiation and other DNA-damaging agents. Similarities and differences to alpha-PAK. J Biol Chem 274:31119-22.
126. Ruan, W., P. Pang, and Y. Rao. 1999. The SH2/SH3 adaptor protein dock interacts with the Ste20-like kinase misshapen in controlling growth cone motility. Neuron 24:595-605.
127. Rudel, T., and G. M. Bokoch. 1997. Membrane and morphological changes in apoptotic cells regulated by caspase-mediated activation of PAK2. Science 276:1571-4.
128. Rudel, T., F. T. Zenke, T. H. Chuang, and G. M. Bokoch. 1998. p21-activated kinase (PAK) is required for Fas-induced JNK activation in Jurkat cells. J Immunol 160:7-11.
129. Russo, M. P., B. L. Bennett, A. M. Manning, D. A. Brenner, and C. Jobin. 2002. Differential requirement for NF-kappaB-inducing kinase in the induction of NF-kappaB by IL-1beta, TNF-alpha, and Fas. Am J Physiol Cell Physiol 283:C347-57.
130. Ruvolo, P. P. 2001. Ceramide regulates cellular homeostasis via diverse stress signaling pathways. Leukemia 15:1153-60.
131. Sabourin, L. A., and M. A. Rudnicki. 1999. Induction of apoptosis by SLK, a Ste20-related kinase. Oncogene 18:7566-75.
132. Sabourin, L. A., K. Tamai, P. Seale, J. Wagner, and M. A. Rudnicki. 2000. Caspase 3 cleavage of the Ste20-related kinase SLK releases and activates an apoptosis-inducing kinase domain and an actin-disassembling region. Mol Cell Biol 20:684-96.
133. Sarin, A., M. L. Wu, and P. A. Henkart. 1996. Different interleukin-1 beta converting enzyme (ICE) family protease requirements for the apoptotic death of T lymphocytes triggered by diverse stimuli. J Exp Med 184:2445-50.
134. Schinkmann, K., and J. Blenis. 1997. Cloning and characterization of a human STE20-like protein kinase with unusual cofactor requirements. J Biol Chem 272:28695-703.
135. Schrick, K., B. Garvik, and L. H. Hartwell. 1997. Mating in Saccharomyces cerevisiae: the role of the pheromone signal transduction pathway in the chemotropic response to pheromone. Genetics 147:19-32.
136. Schurmann, A., A. F. Mooney, L. C. Sanders, M. A. Sells, H. G. Wang, J. C. Reed, and G. M. Bokoch. 2000. p21-activated kinase 1 phosphorylates the death agonist bad and protects cells from apoptosis. Mol Cell Biol 20:453-61.
137. Seo, M., Y. I. Lee, C. H. Cho, C. D. Bae, I. H. Kim, and Y. S. Juhnn. 2002. Bi-directional regulation of UV-induced activation of p38 kinase and c-Jun N-terminal kinase by G protein beta gamma subunits. J Biol Chem.
138. Shi, C. S., J. Tuscano, and J. H. Kehrl. 2000. Adaptor proteins CRK and CRKL associate with the serine/threonine protein kinase GCKR promoting GCKR and SAPK activation. Blood 95:776-82.
139. Shibata, M., T. Yamawaki, T. Sasaki, H. Hattori, J. Hamada, Y. Fukuuchi, H. Okano, and M. Miura. 2002. Upregulation of Akt phosphorylation at the early stage of middle cerebral artery occlusion in mice. Brain Res 942:1-10.
140. Shibuya, H. 1999. [Functional role for TAB1-TAK1 in TGF-beta signaling]. Seikagaku 71:1205-12.
141. Shibuya, H., K. Yamaguchi, K. Shirakabe, A. Tonegawa, Y. Gotoh, N. Ueno, K. Irie, E. Nishida, and K. Matsumoto. 1996. TAB1: an activator of the TAK1 MAPKKK in TGF-beta signal transduction. Science 272:1179-82.
142. Sidhu, J. S., and C. J. Omiecinski. 1998. Protein synthesis inhibitors exhibit a nonspecific effect on phenobarbital-inducible cytochome P450 gene expression in primary rat hepatocytes. J Biol Chem 273:4769-75.
143. Song, H. Y., C. H. Regnier, C. J. Kirschning, D. V. Goeddel, and M. Rothe. 1997. Tumor necrosis factor (TNF)-mediated kinase cascades: bifurcation of nuclear factor-kappaB and c-jun N-terminal kinase (JNK/SAPK) pathways at TNF receptor-associated factor 2. Proc Natl Acad Sci U S A 94:9792-6.
144. Stein, E., U. Huynh-Do, A. A. Lane, D. P. Cerretti, and T. O. Daniel. 1998. Nck recruitment to Eph receptor, EphB1/ELK, couples ligand activation to c-Jun kinase. J Biol Chem 273:1303-8.
145. Stoletov, K. V., K. E. Ratcliffe, S. C. Spring, and B. I. Terman. 2001. NCK and PAK participate in the signaling pathway by which vascular endothelial growth factor stimulates the assembly of focal adhesions. J Biol Chem 276:22748-55.
146. Su, B., J. Cheng, J. Yang, and Z. Guo. 2001. MEKK2 is required for T-cell receptor signals in JNK activation and interleukin-2 gene expression. J Biol Chem 276:14784-90.
147. Su, Y. C., J. Han, S. Xu, M. Cobb, and E. Y. Skolnik. 1997. NIK is a new Ste20-related kinase that binds NCK and MEKK1 and activates the SAPK/JNK cascade via a conserved regulatory domain. Embo J 16:1279-90.
148. Su, Y. C., C. Maurel-Zaffran, J. E. Treisman, and E. Y. Skolnik. 2000. The Ste20 kinase misshapen regulates both photoreceptor axon targeting and dorsal closure, acting downstream of distinct signals. Mol Cell Biol 20:4736-44.
149. Su, Y. C., J. E. Treisman, and E. Y. Skolnik. 1998. The Drosophila Ste20-related kinase misshapen is required for embryonic dorsal closure and acts through a JNK MAPK module on an evolutionarily conserved signaling pathway. Genes Dev 12:2371-80.
150. Sun, H., A. J. King, H. B. Diaz, and M. S. Marshall. 2000. Regulation of the protein kinase Raf-1 by oncogenic Ras through phosphatidylinositol 3-kinase, Cdc42/Rac and Pak. Curr Biol 10:281-4.
151. Swantek, J. L., M. H. Cobb, and T. D. Geppert. 1997. Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) is required for lipopolysaccharide stimulation of tumor necrosis factor alpha (TNF-alpha) translation: glucocorticoids inhibit TNF-alpha translation by blocking JNK/SAPK. Mol Cell Biol 17:6274-82.
152. Takatsu, Y., M. Nakamura, M. Stapleton, M. C. Danos, K. Matsumoto, M. B. O'Connor, H. Shibuya, and N. Ueno. 2000. TAK1 participates in c-Jun N-terminal kinase signaling during Drosophila development. Mol Cell Biol 20:3015-26.
153. Tang, T. K., W. C. Chang, W. H. Chan, S. D. Yang, M. H. Ni, and J. S. Yu. 1998. Proteolytic cleavage and activation of PAK2 during UV irradiation-induced apoptosis in A431 cells. J Cell Biochem 70:442-54.
154. Tang, X., F. R. Khuri, J. J. Lee, B. L. Kemp, D. Liu, W. K. Hong, and L. Mao. 2000. Hypermethylation of the death-associated protein (DAP) kinase promoter and aggressiveness in stage I non-small-cell lung cancer. J Natl Cancer Inst 92:1511-6.
155. Tassi, E., Z. Biesova, P. P. Di Fiore, J. S. Gutkind, and W. T. Wong. 1999. Human JIK, a novel member of the STE20 kinase family that inhibits JNK and is negatively regulated by epidermal growth factor. J Biol Chem 274:33287-95.
156. Tong, T., W. Fan, H. Zhao, S. Jin, F. Fan, P. Blanck, I. Alomo, B. Rajasekaran, Y. Liu, N. J. Holbrook, and Q. Zhan. 2001. Involvement of the MAP kinase pathways in induction of GADD45 following UV radiation. Exp Cell Res 269:64-72.
157. Tsutsumi, T., H. Ushiro, T. Kosaka, T. Kayahara, and K. Nakano. 2000. Proline- and alanine-rich Ste20-related kinase associates with F-actin and translocates from the cytosol to cytoskeleton upon cellular stresses. J Biol Chem 275:9157-62.
158. Tung, R. M., and J. Blenis. 1997. A novel human SPS1/STE20 homologue, KHS, activates Jun N-terminal kinase. Oncogene 14:653-9.
159. Turner, C. E., M. C. Brown, J. A. Perrotta, M. C. Riedy, S. N. Nikolopoulos, A. R. McDonald, S. Bagrodia, S. Thomas, and P. S. Leventhal. 1999. Paxillin LD4 motif binds PAK and PIX through a novel 95-kD ankyrin repeat, ARF-GAP protein: A role in cytoskeletal remodeling. J Cell Biol 145:851-63.
160. Ura, S., N. Masuyama, J. D. Graves, and Y. Gotoh. 2001. Caspase cleavage of MST1 promotes nuclear translocation and chromatin condensation. Proc Natl Acad Sci U S A 98:10148-53.
161. Vacratsis, P. O., B. S. Phinney, D. A. Gage, and K. A. Gallo. 2002. Identification of in vivo phosphorylation sites of MLK3 by mass spectrometry and phosphopeptide mapping. Biochemistry 41:5613-24.
162. Verheijen, M. H., R. M. Wolthuis, J. L. Bos, and L. H. Defize. 1999. The Ras/Erk pathway induces primitive endoderm but prevents parietal endoderm differentiation of F9 embryonal carcinoma cells. J Biol Chem 274:1487-94.
163. Vondriska, T. M., J. B. Klein, and P. Ping. 2001. Use of functional proteomics to investigate PKC epsilon-mediated cardioprotection: the signaling module hypothesis. Am J Physiol Heart Circ Physiol 280:H1434-41.
164. Wagner, C. A., M. Ott, K. Klingel, S. Beck, J. Melzig, B. Friedrich, K. N. Wild, S. Broer, I. Moschen, A. Albers, S. Waldegger, B. Tummler, M. E. Egan, J. P. Geibel, R. Kandolf, and F. Lang. 2001. Effects of the serine/threonine kinase SGK1 on the epithelial Na(+) channel (ENaC) and CFTR: implications for cystic fibrosis. Cell Physiol Biochem 11:209-18.
165. Wajant, H., M. Grell, and P. Scheurich. 1999. TNF receptor associated factors in cytokine signaling. Cytokine Growth Factor Rev 10:15-26.
166. Wajant, H., and P. Scheurich. 2001. Tumor necrosis factor receptor-associated factor (TRAF) 2 and its role in TNF signaling. Int J Biochem Cell Biol 33:19-32.
167. Weston, C. R., and R. J. Davis. 2002. The JNK signal transduction pathway. Curr Opin Genet Dev 12:14-21.
168. Widmann, C., S. Gibson, and G. L. Johnson. 1998. Caspase-dependent cleavage of signaling proteins during apoptosis. A turn-off mechanism for anti-apoptotic signals. J Biol Chem 273:7141-7.
169. Yanagawa, Y., N. Iijima, K. Iwabuchi, and K. Onoe. 2002. Activation of extracellular signal-related kinase by TNF-alpha controls the maturation and function of murine dendritic cells. J Leukoc Biol 71:125-32.
170. Yao, Z., G. Zhou, X. S. Wang, A. Brown, K. Diener, H. Gan, and T. H. Tan. 1999. A novel human STE20-related protein kinase, HGK, that specifically activates the c-Jun N-terminal kinase signaling pathway. J Biol Chem 274:2118-25.
171. Yasufuku-Takano, J., and K. Takano. 2002. [Signal transduction mechanisms of hormones through membrane receptors]. Nippon Rinsho 60:222-9.
172. Yun, T. J., P. M. Chaudhary, G. L. Shu, J. K. Frazer, M. K. Ewings, S. M. Schwartz, V. Pascual, L. E. Hood, and E. A. Clark. 1998. OPG/FDCR-1, a TNF receptor family member, is expressed in lymphoid cells and is up-regulated by ligating CD40. J Immunol 161:6113-21.
173. Yustein, J. T., D. Li, D. Robinson, and H. J. Kung. 2000. KFC, a Ste20-like kinase with mitogenic potential and capability to activate the SAPK/JNK pathway. Oncogene 19:710-8.
174. Zang, M., C. Hayne, and Z. Luo. 2002. Interaction between active Pak1 and Raf-1 is necessary for phosphorylation and activation of Raf-1. J Biol Chem 277:4395-405.
175. Zeng, Q., D. Lagunoff, R. Masaracchia, Z. Goeckeler, G. Cote, and R. Wysolmerski. 2000. Endothelial cell retraction is induced by PAK2 monophosphorylation of myosin II. J Cell Sci 113 ( Pt 3):471-82.
176. Zhou, G., S. C. Lee, Z. Yao, and T. H. Tan. 1999. Hematopoietic progenitor kinase 1 is a component of transforming growth factor beta-induced c-Jun N-terminal kinase signaling cascade. J Biol Chem 274:13133-8.
177. Zhou, T. H., K. Ling, J. Guo, H. Zhou, Y. L. Wu, Q. Jing, L. Ma, and G. Pei. 2000. Identification of a human brain-specific isoform of mammalian STE20-like kinase 3 that is regulated by cAMP-dependent protein kinase. J Biol Chem 275:2513-9.