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• W2054865251 abstract "We have cloned a novel human GCK family kinase that has been designated as MASK (Mst3 andSOK1-related kinase). MASK is widely expressed and encodes a protein of 416 amino acid residues, with an N-terminal kinase domain and a unique C-terminal region. Like other GCK-III subfamily kinases, MASK does not activate any mitogen-activated protein kinase pathways. Wild type MASK, but not a form lacking the C terminus, exhibits homophilic binding in the yeast two-hybrid system and in coimmunoprecipitation experiments. Additionally, deletion of this C-terminal region of MASK leads to an increased kinase activity toward itself as well as toward an exogenous substrate, myelin basic protein. A potential caspase 3 cleavage site (DESDS) is present in the C-terminal region of MASK, and we show that MASK is cleaved in vitro by caspase 3. Finally, wild type and C-terminally truncated forms of MASK can both induce apoptosis upon overexpression in mammalian cells that is abrogated by CrmA, suggesting involvement of MASK in the apoptotic machinery in mammalian cells. We have cloned a novel human GCK family kinase that has been designated as MASK (Mst3 andSOK1-related kinase). MASK is widely expressed and encodes a protein of 416 amino acid residues, with an N-terminal kinase domain and a unique C-terminal region. Like other GCK-III subfamily kinases, MASK does not activate any mitogen-activated protein kinase pathways. Wild type MASK, but not a form lacking the C terminus, exhibits homophilic binding in the yeast two-hybrid system and in coimmunoprecipitation experiments. Additionally, deletion of this C-terminal region of MASK leads to an increased kinase activity toward itself as well as toward an exogenous substrate, myelin basic protein. A potential caspase 3 cleavage site (DESDS) is present in the C-terminal region of MASK, and we show that MASK is cleaved in vitro by caspase 3. Finally, wild type and C-terminally truncated forms of MASK can both induce apoptosis upon overexpression in mammalian cells that is abrogated by CrmA, suggesting involvement of MASK in the apoptotic machinery in mammalian cells. The GCK 1GCKgerminal center kinasePAKp21-activated kinaseSte20Sterile 20SOK1Ste20-like oxidant-stress responsive kinase 1JNKJun N terminus kinaseMAPKmitogen-activated protein kinase, SOK1, Ste20-like oxidant stress response kinase-1YSK1yeast Ste20-related kinase 1Mstmammalian sterile twenty-likeKrskinase responsive to stressMASKMst3 and SOK1-related kinaseESTexpression sequence tagUTRuntranslated regionRTreverse transcriptionHAhemagglutininTAK1transformation activating kinase 1TAB1TAK1-binding protein 1MBPmyelin basic proteinGSTglutathione S-transferaseATFactivating transcription factorEGFRepidermal growth factor receptormAbmonoclonal antibodyILinterleukinSLKSte20 like kinaseHPK1hematopoietic progenitor kinase 1BACbacterial artificial chromosomeOSR1oxidative stress responsive 1ERKextracellular signal-regulated kinaseMEKK1MAPK/ERK kinase kinase 1X-gal5-bromo-4-chloro-3-indolyl β-d-galactopyranosideTNFtumor necrosis factorMOPS4-morpholinepropanesulfonic acidELAMendothelial leukocyte adhesion moleculeGFPgreen fluorescence proteinWTwild typeTRAF2TNF receptor-associated factor 2 1GCKgerminal center kinasePAKp21-activated kinaseSte20Sterile 20SOK1Ste20-like oxidant-stress responsive kinase 1JNKJun N terminus kinaseMAPKmitogen-activated protein kinase, SOK1, Ste20-like oxidant stress response kinase-1YSK1yeast Ste20-related kinase 1Mstmammalian sterile twenty-likeKrskinase responsive to stressMASKMst3 and SOK1-related kinaseESTexpression sequence tagUTRuntranslated regionRTreverse transcriptionHAhemagglutininTAK1transformation activating kinase 1TAB1TAK1-binding protein 1MBPmyelin basic proteinGSTglutathione S-transferaseATFactivating transcription factorEGFRepidermal growth factor receptormAbmonoclonal antibodyILinterleukinSLKSte20 like kinaseHPK1hematopoietic progenitor kinase 1BACbacterial artificial chromosomeOSR1oxidative stress responsive 1ERKextracellular signal-regulated kinaseMEKK1MAPK/ERK kinase kinase 1X-gal5-bromo-4-chloro-3-indolyl β-d-galactopyranosideTNFtumor necrosis factorMOPS4-morpholinepropanesulfonic acidELAMendothelial leukocyte adhesion moleculeGFPgreen fluorescence proteinWTwild typeTRAF2TNF receptor-associated factor 2 family, together with the PAK family, comprises the Ste20 group of kinases in higher eukaryotes (1Dan I. Watanabe N.M. Kusumi A. Trends Cell Biol. 2001; 11: 220-230Abstract Full Text Full Text PDF PubMed Scopus (501) Google Scholar). The GCK family represents a rather large family of protein kinases with over twenty members identified in humans thus far (1Dan I. Watanabe N.M. Kusumi A. Trends Cell Biol. 2001; 11: 220-230Abstract Full Text Full Text PDF PubMed Scopus (501) Google Scholar). These kinases are involved in diverse cellular events ranging from cytoskeletal rearrangement and morphogenesis to apoptosis (1Dan I. Watanabe N.M. Kusumi A. Trends Cell Biol. 2001; 11: 220-230Abstract Full Text Full Text PDF PubMed Scopus (501) Google Scholar). Most notably, they regulate JNK or p38 MAPK signaling pathways during these processes (1Dan I. Watanabe N.M. Kusumi A. Trends Cell Biol. 2001; 11: 220-230Abstract Full Text Full Text PDF PubMed Scopus (501) Google Scholar, 2Kyriakis J.M. J. Biol. Chem. 1999; 274: 5259-5262Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 3Widmann C. Gibson S. Jarpe M.B. Johnson G.L. Physiol. Rev. 1999; 79: 143-180Crossref PubMed Scopus (2245) Google Scholar, 4Kyriakis J.M. Avruch J. Physiol. Rev. 2001; 81: 807-869Crossref PubMed Scopus (2847) Google Scholar).The GCK family members are distinguished from PAK family kinases in that they have a kinase domain at their N terminus instead of at the C terminus, as is the case with PAK kinases (1Dan I. Watanabe N.M. Kusumi A. Trends Cell Biol. 2001; 11: 220-230Abstract Full Text Full Text PDF PubMed Scopus (501) Google Scholar, 2Kyriakis J.M. J. Biol. Chem. 1999; 274: 5259-5262Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar). Indeed, although the kinase domain operationally defines this family, the non-catalytic regions likely direct the scope of intermolecular interactions and may be responsible for functional distinctions between various family members (1Dan I. Watanabe N.M. Kusumi A. Trends Cell Biol. 2001; 11: 220-230Abstract Full Text Full Text PDF PubMed Scopus (501) Google Scholar). As the number of identified GCK family kinases has increased, so has the variety of non-catalytic regions of these molecules (1Dan I. Watanabe N.M. Kusumi A. Trends Cell Biol. 2001; 11: 220-230Abstract Full Text Full Text PDF PubMed Scopus (501) Google Scholar). The GCK family was historically classified into two subfamilies, but recent extensive analyses on human,Drosophila, and Caenorhabditis elegans genomes has led to their reclassification into eight phylogenetically distinct subfamilies (1Dan I. Watanabe N.M. Kusumi A. Trends Cell Biol. 2001; 11: 220-230Abstract Full Text Full Text PDF PubMed Scopus (501) Google Scholar, 2Kyriakis J.M. J. Biol. Chem. 1999; 274: 5259-5262Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar). In the newly established phylogenetic relationship, each subfamily is represented by a distinct Drosophila andC. elegans kinase with two to four human orthologs (1Dan I. Watanabe N.M. Kusumi A. Trends Cell Biol. 2001; 11: 220-230Abstract Full Text Full Text PDF PubMed Scopus (501) Google Scholar). One of the most crucial subjects in the study of the mammalian GCK family kinases in the post-genome era is to establish distinct features of a kinase in reference to the other members in the same subfamily and to kinases in different subfamilies. In this sense, the most peculiar subfamily may be the GCK-III subfamily consisting of two mammalian kinases, SOK1/YSK1 and Mst3, and their Drosophilaand C. elegans orthologs, CG5169 and T19A5.2 (1Dan I. Watanabe N.M. Kusumi A. Trends Cell Biol. 2001; 11: 220-230Abstract Full Text Full Text PDF PubMed Scopus (501) Google Scholar, 5Schinkmann K. Blenis J. J. Biol. Chem. 1997; 272: 28695-28703Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 6Pombo C.M. Bonventre J.V. Molnar A. Kyriakis J.M. Force T. EMBO J. 1996; 15: 4537-4546Crossref PubMed Scopus (133) Google Scholar, 7Osada S. Izawa M. Saito R. Mizuno K. Suzuki A. Hirai S. Ohno S. Oncogene. 1997; 14: 2047-2057Crossref PubMed Scopus (30) Google Scholar). Unlike other GCK family kinases, neither SOK1/YSK1 nor Mst3 has been shown to activate JNK or p38 MAPK pathways (5Schinkmann K. Blenis J. J. Biol. Chem. 1997; 272: 28695-28703Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 6Pombo C.M. Bonventre J.V. Molnar A. Kyriakis J.M. Force T. EMBO J. 1996; 15: 4537-4546Crossref PubMed Scopus (133) Google Scholar, 7Osada S. Izawa M. Saito R. Mizuno K. Suzuki A. Hirai S. Ohno S. Oncogene. 1997; 14: 2047-2057Crossref PubMed Scopus (30) Google Scholar). The only distinct physiological function demonstrated to date is an activation of SOK1 by oxidant stress and chemical anoxia (6Pombo C.M. Bonventre J.V. Molnar A. Kyriakis J.M. Force T. EMBO J. 1996; 15: 4537-4546Crossref PubMed Scopus (133) Google Scholar, 8Pombo C.M. Tsujita T. Kyriakis J.M. Bonventre J.V. Force T. J. Biol. Chem. 1997; 272: 29372-29377Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). Although GCK-IIIs are closely related to GCK-IIs, including Mst1/Krs2 and Mst2/Krs1, which are activated during apoptosis, no involvement in apoptosis has been reported for GCK-IIIs thus far (9Creasy C.L. Chernoff J. J. Biol. Chem. 1995; 270: 21695-21700Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 10Creasy C.L. Chernoff J. Gene. 1995; 167: 303-306Crossref PubMed Scopus (118) Google Scholar, 11Taylor L.K. Wang H.C. Erikson R.L. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 10099-10104Crossref PubMed Scopus (141) Google Scholar, 12Lee K.K. Murakawa M. Nishida E. Tsubuki S. Kawashima S. Sakamaki K. Yonehara S. Oncogene. 1998; 16: 3029-3037Crossref PubMed Scopus (119) Google Scholar, 13Graves J.D. Gotoh Y. Draves K.E. Ambrose D. Han D.K. Wright M. Chernoff J. Clark E.A. Krebs E.G. EMBO J. 1998; 17: 2224-2234Crossref PubMed Scopus (322) Google Scholar).Here, we report cloning of a novel kinase of the GCK-III subfamily that has been designated MASK (Mst3 andSOK1-related kinase), whose existence was first described in our systematic screening of Ste20 group kinases in the human genome (1Dan I. Watanabe N.M. Kusumi A. Trends Cell Biol. 2001; 11: 220-230Abstract Full Text Full Text PDF PubMed Scopus (501) Google Scholar). Shortly after our first mention of MASKgene, another group described an identical gene as MST4 and showed that it is a kinase but did not assign any function (14Qian Z. Lin C. Espinosa R. LeBeau M. Rosner M.R. J. Biol. Chem. 2001; 276: 22439-22445Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar). MASK is a protein kinase ubiquitously expressed in most tissues. Analogous to other GCK-III subfamily members, MASK was found to activate none of the MAPK pathways. The C-terminal non-catalytic region of MASK is involved in self-association and is inhibitory to its kinase activity. Using a polyclonal antibody generated against the C terminus of MASK, we show that it is expressed as a 47-kDa protein in several cell lines. MASK is cleaved in vitro by caspase 3 to generate a C-terminally truncated form presumably cleaved at a putative caspase 3 cleavage site. Most notably, both full-length and C-terminally truncated forms of MASK, but not a kinase dead version, induce apoptosis when overexpressed in MCF-7 human breast carcinoma cells and human embryonic kidney 293 cells. This apoptotic effect is abrogated upon coexpression of CrmA, a virally encoded inhibitor of caspases. Finally, a kinase dead version of MASK cannot inhibit apoptosis induced by the TNF receptor. Taken together, our results implicate MASK in the apoptotic pathways in cells.DISCUSSIONThe GCK family of protein kinases represents an emerging large family of protein kinases with eight subfamilies (1Dan I. Watanabe N.M. Kusumi A. Trends Cell Biol. 2001; 11: 220-230Abstract Full Text Full Text PDF PubMed Scopus (501) Google Scholar, 2Kyriakis J.M. J. Biol. Chem. 1999; 274: 5259-5262Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar). To study such a large family of protein kinases, a phylogenetic analysis is indispensable. Most of the GCK family of protein kinases characterized so far activate either JNK or p38 MAPK signaling pathways upon overexpression (1Dan I. Watanabe N.M. Kusumi A. Trends Cell Biol. 2001; 11: 220-230Abstract Full Text Full Text PDF PubMed Scopus (501) Google Scholar, 2Kyriakis J.M. J. Biol. Chem. 1999; 274: 5259-5262Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 3Widmann C. Gibson S. Jarpe M.B. Johnson G.L. Physiol. Rev. 1999; 79: 143-180Crossref PubMed Scopus (2245) Google Scholar, 4Kyriakis J.M. Avruch J. Physiol. Rev. 2001; 81: 807-869Crossref PubMed Scopus (2847) Google Scholar). However, there are several exceptions to this rule. LOK from the GCK-V subfamily does not activate either pathway, but its closely related homolog SLK activates JNK (25Sabourin L.A. Rudnicki M.A. Oncogene. 1999; 18: 7566-7575Crossref PubMed Scopus (68) Google Scholar, 35Kuramochi S. Moriguchi T. Kuida K. Endo J. Semba K. Nishida E. Karasuyama H. J. Biol. Chem. 1997; 272: 22679-22684Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar). OSR1 from the GCK-VI subfamily is yet to be shown to activate either pathway, but its homolog PASK/SPAK activates p38 MAPK (36Tamari M. Daigo Y. Nakamura Y. J. Hum. Genet. 1999; 44: 116-120Crossref PubMed Scopus (51) Google Scholar, 37Ushiro H. Tsutsumi T. Suzuki K. Kayahara T. Nakano K. Arch. Biochem. Biophys. 1998; 355: 233-240Crossref PubMed Scopus (72) Google Scholar, 38Johnston A.M. Naselli G. Gonez L.J. Martin R.M. Harrison L.C. DeAizpurua H.J. Oncogene. 2000; 19: 4290-4297Crossref PubMed Scopus (115) Google Scholar). Therefore, these kinases may be able to activate either pathway under different physiological conditions. Studies addressing the involvement of the most recent members of the GCK-VII subfamily, MYO3A and MYO3B, in MAPK signaling pathways are underway (39Dose A.C. Burnside B. Genomics. 2000; 67: 333-342Crossref PubMed Scopus (54) Google Scholar). 2A. C. Dose, personal communication. The most notable exceptions are found in the GCK-III subfamily of kinases consisting of SOK1/YSK1 and Mst3 in addition to MASK, which is described in this report. All of them are active kinases when overexpressed but do not activate JNK or p38 MAPK pathways (5Schinkmann K. Blenis J. J. Biol. Chem. 1997; 272: 28695-28703Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 6Pombo C.M. Bonventre J.V. Molnar A. Kyriakis J.M. Force T. EMBO J. 1996; 15: 4537-4546Crossref PubMed Scopus (133) Google Scholar, 7Osada S. Izawa M. Saito R. Mizuno K. Suzuki A. Hirai S. Ohno S. Oncogene. 1997; 14: 2047-2057Crossref PubMed Scopus (30) Google Scholar). However, it is possible that they participate in other less characterized MAPK pathways such as ERK3/4 or ERK5 (3Widmann C. Gibson S. Jarpe M.B. Johnson G.L. Physiol. Rev. 1999; 79: 143-180Crossref PubMed Scopus (2245) Google Scholar).Four GCK family kinases, Mst1/Krs2, Mst2/Krs1 (GCK-II), HPK1 (GCK-1), and SLK (GCK-V) have been reported to be directly or indirectly involved in apoptosis to date (1Dan I. Watanabe N.M. Kusumi A. Trends Cell Biol. 2001; 11: 220-230Abstract Full Text Full Text PDF PubMed Scopus (501) Google Scholar, 12Lee K.K. Murakawa M. Nishida E. Tsubuki S. Kawashima S. Sakamaki K. Yonehara S. Oncogene. 1998; 16: 3029-3037Crossref PubMed Scopus (119) Google Scholar, 13Graves J.D. Gotoh Y. Draves K.E. Ambrose D. Han D.K. Wright M. Chernoff J. Clark E.A. Krebs E.G. EMBO J. 1998; 17: 2224-2234Crossref PubMed Scopus (322) Google Scholar, 24Chen Y.R. Meyer C.F. Ahmed B. Yao Z. Tan T.H. Oncogene. 1999; 18: 7370-7377Crossref PubMed Scopus (67) Google Scholar, 25Sabourin L.A. Rudnicki M.A. Oncogene. 1999; 18: 7566-7575Crossref PubMed Scopus (68) Google Scholar). They are suggested to be activated upon cleavage by caspase 3 to produce the free kinase domain with enhanced activity during apoptosis (1Dan I. Watanabe N.M. Kusumi A. Trends Cell Biol. 2001; 11: 220-230Abstract Full Text Full Text PDF PubMed Scopus (501) Google Scholar, 12Lee K.K. Murakawa M. Nishida E. Tsubuki S. Kawashima S. Sakamaki K. Yonehara S. Oncogene. 1998; 16: 3029-3037Crossref PubMed Scopus (119) Google Scholar, 13Graves J.D. Gotoh Y. Draves K.E. Ambrose D. Han D.K. Wright M. Chernoff J. Clark E.A. Krebs E.G. EMBO J. 1998; 17: 2224-2234Crossref PubMed Scopus (322) Google Scholar, 24Chen Y.R. Meyer C.F. Ahmed B. Yao Z. Tan T.H. Oncogene. 1999; 18: 7370-7377Crossref PubMed Scopus (67) Google Scholar, 25Sabourin L.A. Rudnicki M.A. Oncogene. 1999; 18: 7566-7575Crossref PubMed Scopus (68) Google Scholar). This may also be the case with MASK for two reasons. First, both wild type and C terminus-truncated forms of MASK can induce apoptosis of cultured cells upon overexpression. Second, MASK can be cleaved by caspase 3 in vitro. Our findings indicate that the pro-apoptotic effect of MASK is enhanced by loss of the region C-terminal to the putative caspase cleavage site. In addition, this effect is abrogated upon treatment with a caspase inhibitor, CrmA. Because activation of the NF-κB pathway confers protection against apoptosis in several instances, the lack of activation of this pathway is consistent with the apoptosis-inducing ability of MASK (40Taglialatela G. Robinson R. Perez-Polo J.R. J. Neurosci. Res. 1997; 47: 155-162Crossref PubMed Scopus (156) Google Scholar). Given these observations, it is possible that MASK participates in the apoptotic cascade in cells. Whether this involvement in apoptosis is specific to MASK or common to other GCK-III subfamily members is yet to be tested. SOK1 is activated during the initial stages of chemical anoxia-induced necrotic cell death, but its involvement in apoptosis remains uncertain (8Pombo C.M. Tsujita T. Kyriakis J.M. Bonventre J.V. Force T. J. Biol. Chem. 1997; 272: 29372-29377Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). Because the recognition motif for caspase 3 is present only in MASK, it may be that the induction of apoptosis is a property restricted to MASK.The demonstration that overexpression of MASK alone is sufficient to induce apoptosis is interesting for several reasons. Like other GCK-IIIs, MASK is ubiquitously expressed among tissues that do not undergo apoptosis under physiological conditions (5Schinkmann K. Blenis J. J. Biol. Chem. 1997; 272: 28695-28703Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 6Pombo C.M. Bonventre J.V. Molnar A. Kyriakis J.M. Force T. EMBO J. 1996; 15: 4537-4546Crossref PubMed Scopus (133) Google Scholar, 7Osada S. Izawa M. Saito R. Mizuno K. Suzuki A. Hirai S. Ohno S. Oncogene. 1997; 14: 2047-2057Crossref PubMed Scopus (30) Google Scholar). Thus endogenous MASK is likely to be silenced so as not to induce apoptosis in the normal intracellular environment. Our demonstration that a fraction of the overexpressed MASK remains resistant to caspase 3 cleavage suggests that there might exist a protective mechanism that keeps MASK from participating in apoptotic events. One of such mechanisms is steric inhibition by oligomerization. Indeed, we have shown by yeast two-hybrid analysis and in vivo experiments that the direct self-association of MASK molecules requires its C terminus region. The C terminus region corresponding to 359–391 amino acids is predicted to form a coiled-coil motif, which often mediates oligomerization (26Wolf E. Kim P.S. Berger B. Protein Sci. 1997; 6: 1179-1189Crossref PubMed Scopus (646) Google Scholar, 30Burkhard P. Stetefeld J. Strelkov S.V. Trends Cell Biol. 2001; 11: 82-88Abstract Full Text Full Text PDF PubMed Scopus (838) Google Scholar). Another possibility is involvement of inhibitory factors, which are yet to be found. To determine whether the oligomerization of MASK regulates apoptosis especially by preventing cleavage requires further studies.The GCK-II subfamily kinases consisting of Mst1/Krs2 and Mst2/Krs1 are also known to induce apoptosis (12Lee K.K. Murakawa M. Nishida E. Tsubuki S. Kawashima S. Sakamaki K. Yonehara S. Oncogene. 1998; 16: 3029-3037Crossref PubMed Scopus (119) Google Scholar, 13Graves J.D. Gotoh Y. Draves K.E. Ambrose D. Han D.K. Wright M. Chernoff J. Clark E.A. Krebs E.G. EMBO J. 1998; 17: 2224-2234Crossref PubMed Scopus (322) Google Scholar). However, their mechanism of action seems different from that of MASK. Mst1 activates JNK and p38 pathways during apoptosis (13Graves J.D. Gotoh Y. Draves K.E. Ambrose D. Han D.K. Wright M. Chernoff J. Clark E.A. Krebs E.G. EMBO J. 1998; 17: 2224-2234Crossref PubMed Scopus (322) Google Scholar). Recent observations suggest that Mst1 acts directly upstream of a MAPK kinase kinase, MEKK1 (41Graves J.D. Draves K.E. Gotoh Y. Krebs E.G. Clark E.A. J. Biol. Chem. 2001; 276: 14909-14915Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar). This is unlikely to be the case with MASK, which probably induces apoptosis via some other pathway. We have shown that the kinase activity of MASK is necessary for its induction of apoptosis, but its physiological phosphorylation substrate is still unidentified.Points of similarity that we have noticed between MASK and Mst1 are their ability to oligomerize and the inhibitory effect on kinase activity of their respective C-terminal regions. Creasy et al. (29Creasy C.L. Ambrose D.M. Chernoff J. J. Biol. Chem. 1996; 271: 21049-21053Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar) have identified two distinct domains in the C-terminal region of Mst1, a dimerization domain and an inhibitory domain that reduces its kinase activity. Multicoil computer program predicts MASK to prefer a higher degree of oligomerization whereas Mst1 has been shown to dimerize by cross-linking experiments (26Wolf E. Kim P.S. Berger B. Protein Sci. 1997; 6: 1179-1189Crossref PubMed Scopus (646) Google Scholar, 29Creasy C.L. Ambrose D.M. Chernoff J. J. Biol. Chem. 1996; 271: 21049-21053Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar). GCK-II, GCK-III, and GCK-VI subfamily kinases are often put together in the same category due to presence of a short C terminus region, but such an oversimplification should be avoided inasmuch as their C terminus regions are structurally distinct from each other (1Dan I. Watanabe N.M. Kusumi A. Trends Cell Biol. 2001; 11: 220-230Abstract Full Text Full Text PDF PubMed Scopus (501) Google Scholar).While this report was in preparation, a report describing the cloning of a gene, designated MST4, that is identical toMASK was published (14Qian Z. Lin C. Espinosa R. LeBeau M. Rosner M.R. J. Biol. Chem. 2001; 276: 22439-22445Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar). The cDNA reported for Mst4 is 1372 bp, whereas the length of MASK cDNA that we have cloned is 3263 bp. Given that our Northern blot shows a single band migrating at ∼3.3 kb, it is likely that we have identified the full-length cDNA, whereas the Mst4 sequence represents a partial clone. Nevertheless, both of the cDNAs contain the entire open reading frame and code for the same protein of 416 amino acids. Additionally, Qian et al. (14Qian Z. Lin C. Espinosa R. LeBeau M. Rosner M.R. J. Biol. Chem. 2001; 276: 22439-22445Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar) have described an alternatively spliced transcript that they designate as Mst4a, which encodes a protein of 354 amino acids. Although, the role of Mst4/MASK in apoptosis was not investigated, Qian et al. (14Qian Z. Lin C. Espinosa R. LeBeau M. Rosner M.R. J. Biol. Chem. 2001; 276: 22439-22445Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar) also did not detect any activation of ERK, p38, or JNK MAPK pathways upon overexpression of Mst4/MASK.In conclusion, we have identified and cloned a novel GCK family kinase,MASK, that belongs to the GCK-III subfamily. MASK shows widespread expression and does not activate ERK, p38, JNK, or NF-κB pathways. The C-terminal region of MASK is essential for its self-association and has an inhibitory effect on its kinase activity. The C-terminal region can be cleaved by caspase 3 in vitro. Most importantly, MASK and its C-terminal truncated form can induce apoptosis upon overexpression, with the latter inducing a more potent apoptotic effect. These findings represent an important step toward elucidating the physiological role of MASK and other GCK-III subfamily kinases. The GCK 1GCKgerminal center kinasePAKp21-activated kinaseSte20Sterile 20SOK1Ste20-like oxidant-stress responsive kinase 1JNKJun N terminus kinaseMAPKmitogen-activated protein kinase, SOK1, Ste20-like oxidant stress response kinase-1YSK1yeast Ste20-related kinase 1Mstmammalian sterile twenty-likeKrskinase responsive to stressMASKMst3 and SOK1-related kinaseESTexpression sequence tagUTRuntranslated regionRTreverse transcriptionHAhemagglutininTAK1transformation activating kinase 1TAB1TAK1-binding protein 1MBPmyelin basic proteinGSTglutathione S-transferaseATFactivating transcription factorEGFRepidermal growth factor receptormAbmonoclonal antibodyILinterleukinSLKSte20 like kinaseHPK1hematopoietic progenitor kinase 1BACbacterial artificial chromosomeOSR1oxidative stress responsive 1ERKextracellular signal-regulated kinaseMEKK1MAPK/ERK kinase kinase 1X-gal5-bromo-4-chloro-3-indolyl β-d-galactopyranosideTNFtumor necrosis factorMOPS4-morpholinepropanesulfonic acidELAMendothelial leukocyte adhesion moleculeGFPgreen fluorescence proteinWTwild typeTRAF2TNF receptor-associated factor 2 1GCKgerminal center kinasePAKp21-activated kinaseSte20Sterile 20SOK1Ste20-like oxidant-stress responsive kinase 1JNKJun N terminus kinaseMAPKmitogen-activated protein kinase, SOK1, Ste20-like oxidant stress response kinase-1YSK1yeast Ste20-related kinase 1Mstmammalian sterile twenty-likeKrskinase responsive to stressMASKMst3 and SOK1-related kinaseESTexpression sequence tagUTRuntranslated regionRTreverse transcriptionHAhemagglutininTAK1transformation activating kinase 1TAB1TAK1-binding protein 1MBPmyelin basic proteinGSTglutathione S-transferaseATFactivating transcription factorEGFRepidermal growth factor receptormAbmonoclonal antibodyILinterleukinSLKSte20 like kinaseHPK1hematopoietic progenitor kinase 1BACbacterial artificial chromosomeOSR1oxidative stress responsive 1ERKextracellular signal-regulated kinaseMEKK1MAPK/ERK kinase kinase 1X-gal5-bromo-4-chloro-3-indolyl β-d-galactopyranosideTNFtumor necrosis factorMOPS4-morpholinepropanesulfonic acidELAMendothelial leukocyte adhesion moleculeGFPgreen fluorescence proteinWTwild typeTRAF2TNF receptor-associated factor 2 family, together with the PAK family, comprises the Ste20 group of kinases in higher eukaryotes (1Dan I. Watanabe N.M. Kusumi A. Trends Cell Biol. 2001; 11: 220-230Abstract Full Text Full Text PDF PubMed Scopus (501) Google Scholar). The GCK family represents a rather large family of protein kinases with over twenty members identified in humans thus far (1Dan I. Watanabe N.M. Kusumi A. Trends Cell Biol. 2001; 11: 220-230Abstract Full Text Full Text PDF PubMed Scopus (501) Google Scholar). These kinases are involved in diverse cellular events ranging from cytoskeletal rearrangement and morphogenesis to apoptosis (1Dan I. Watanabe N.M. Kusumi A. Trends Cell Biol. 2001; 11: 220-230Abstract Full Text Full Text PDF PubMed Scopus (501) Google Scholar). Most notably, they regulate JNK or p38 MAPK signaling pathways during these processes (1Dan I. Watanabe N.M. Kusumi A. Trends Cell Biol. 2001; 11: 220-230Abstract Full Text Full Text PDF PubMed Scopus (501) Google Scholar, 2Kyriakis J.M. J. Biol. Chem. 1999; 274: 5259-5262Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 3Widmann C. Gibson S. Jarpe M.B. Johnson G.L. Physiol. Rev. 1999; 79: 143-180Crossref PubMed Scopus (2245) Google Scholar, 4Kyriakis J.M. Avruch J. Physiol. 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• W2054865251 title "Cloning of MASK, a Novel Member of the Mammalian Germinal Center Kinase III Subfamily, with Apoptosis-inducing Properties" @default.
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