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• W2018162912 abstract "To elucidate the function of keratins 8 and 18 (K8/18), major components of the intermediate filaments of simple epithelia, we searched for K8/18-binding proteins by screening a yeast two-hybrid library. We report here that human Mrj, a DnaJ/Hsp40 family protein, directly binds to K18. Among the interactions between DnaJ/Hsp40 family proteins and various intermediate filament proteins that we tested using two-hybrid methods, Mrj specifically interacted with K18. Immunostaining with anti-Mrj antibody showed that Mrj colocalized with K8/18 filaments in HeLa cells. Mrj was immunoprecipitated not only with K18, but also with the stress-induced and constitutively expressed heat shock protein Hsp/c70. Mrj bound to K18 through its C terminus and interacted with Hsp/c70 via its N terminus, which contains the J domain. Microinjection of anti-Mrj antibody resulted in the disorganization of K8/18 filaments, without effects on the organization of actin filaments and microtubules. Taken together, these results suggest that Mrj may play an important role in the regulation of K8/18 filament organization as a K18-specific co-chaperone working together with Hsp/c70. To elucidate the function of keratins 8 and 18 (K8/18), major components of the intermediate filaments of simple epithelia, we searched for K8/18-binding proteins by screening a yeast two-hybrid library. We report here that human Mrj, a DnaJ/Hsp40 family protein, directly binds to K18. Among the interactions between DnaJ/Hsp40 family proteins and various intermediate filament proteins that we tested using two-hybrid methods, Mrj specifically interacted with K18. Immunostaining with anti-Mrj antibody showed that Mrj colocalized with K8/18 filaments in HeLa cells. Mrj was immunoprecipitated not only with K18, but also with the stress-induced and constitutively expressed heat shock protein Hsp/c70. Mrj bound to K18 through its C terminus and interacted with Hsp/c70 via its N terminus, which contains the J domain. Microinjection of anti-Mrj antibody resulted in the disorganization of K8/18 filaments, without effects on the organization of actin filaments and microtubules. Taken together, these results suggest that Mrj may play an important role in the regulation of K8/18 filament organization as a K18-specific co-chaperone working together with Hsp/c70. intermediate filaments keratin amino acids glutathioneS-transferase glial fibrillary acidic protein Intermediate filaments (IFs)1 are major components of the cytoskeleton and nuclear envelope in most types of eukaryotic cells (1Lazarides E. Nature. 1980; 283: 249-256Crossref PubMed Scopus (1433) Google Scholar, 2Franke W.W. Cell. 1987; 48: 3-4Abstract Full Text PDF PubMed Scopus (160) Google Scholar, 3Steinert P.M. Liem R.K. Cell. 1990; 60: 521-523Abstract Full Text PDF PubMed Scopus (140) Google Scholar, 4Skalli O. Goldman R.D. Cell Motil. Cytoskeleton. 1991; 19: 67-79Crossref PubMed Scopus (136) Google Scholar, 5Fuchs E. Weber K. Annu. Rev. Biochem. 1994; 63: 345-382Crossref PubMed Scopus (1272) Google Scholar, 6Fuchs E. Cleveland D.W. Science. 1998; 279: 514-519Crossref PubMed Scopus (828) Google Scholar). Although structural components of other major cytoskeletal proteins (actin and tubulin) are highly conserved in different cell types, the constituent proteins of IFs show intriguing molecular diversities and are expressed in tissue-specific programs, which makes them ideal molecular markers for the differentiation state in developmental biology and pathology (7Steinert P.M. Roop D.R. Annu. Rev. Biochem. 1988; 57: 593-625Crossref PubMed Scopus (1119) Google Scholar). Cytoplasmic IFs are usually organized into 10-nm diameter fibers that are prevalent in the perinuclear region, where they appear to be attached to the outer nuclear envelope membrane or to nuclear pore complexes (4Skalli O. Goldman R.D. Cell Motil. Cytoskeleton. 1991; 19: 67-79Crossref PubMed Scopus (136) Google Scholar). Continuous with this perinuclear array, IFs extend radially through the cytoplasm, eventually forming a close association with the plasma membrane. The intracellular IF networks were thought to be relatively stable in comparison with other cytoskeletal components such as actin filaments and microtubules; however, IFs have dynamic properties (8Inagaki M. Nakamura Y. Takeda M. Nishimura T. Inagaki N. Brain Pathol. 1994; 4: 239-243Crossref PubMed Scopus (124) Google Scholar, 9Inagaki M. Matsuoka Y. Tsujimura K. Ando S. Tokui T. Takahashi T. Inagaki N. Bioessays. 1996; 18: 481-487Crossref Scopus (160) Google Scholar). Accumulating data strongly suggest that assembly and disassembly of IF organization are regulated by the site-specific phosphorylation state of IFs (9Inagaki M. Matsuoka Y. Tsujimura K. Ando S. Tokui T. Takahashi T. Inagaki N. Bioessays. 1996; 18: 481-487Crossref Scopus (160) Google Scholar, 10Inagaki M. Nishi Y. Nishizawa K. Matsuyama M. Sato C. Nature. 1987; 328: 649-652Crossref PubMed Scopus (334) Google Scholar, 11Eriksson J.E. Opal P. Goldman R.D. Curr. Opin. Cell Biol. 1992; 4: 99-104Crossref PubMed Scopus (126) Google Scholar), which is determined by kinase/phosphatase equilibria (11Eriksson J.E. Opal P. Goldman R.D. Curr. Opin. Cell Biol. 1992; 4: 99-104Crossref PubMed Scopus (126) Google Scholar, 12Yano T. Tokui T. Nishi Y. Nishizawa K. Shibata M. Kikuchi K. Tsuiki S. Yamauchi T. Inagaki M. Eur. J. Biochem. 1991; 197: 281-290Crossref PubMed Scopus (80) Google Scholar, 13Toivola D.M. Goldman R.D. Garrod D.R. Eriksson J.E. J. Cell Sci. 1997; 110: 23-33Crossref PubMed Google Scholar, 14Inada H. Togashi H. Nakamura Y. Kaibuchi K. Nagata K. Inagaki M. J. Biol. Chem. 1999; 274: 34932-34939Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar).The keratin subfamily, which is preferentially expressed in epithelial cells, has over 20 members (keratins 1–20) that form obligate noncovalent heteropolymers of at least one type I keratin (keratins 9–20) and one type II keratin (keratins 1–8) (15Moll R. Franke W.W. Schiller D.L. Geiger B. Krepler R. Cell. 1982; 31: 11-24Abstract Full Text PDF PubMed Scopus (4495) Google Scholar). In epithelial cells, keratin filaments are typically organized in a cytoplasmic reticular network of anastomosing filament bundles involving their noncovalent linkage at the surface of the nucleus and at cell adhesion complexes. This adhesion machinery consists of desmosomes, which mediate adhesion between cells, and hemidesmosomes, which mediate the adhesion of epithelial cells to the underlying basal lamina. One role that has been ascribed to various keratin filament networks of stratified squamous epithelia is to impart mechanical integrity to cells, without which the cells become fragile and prone to rupture (16Hutton E. Paladini R.D., Yu, Q.C. Yen M. Coulombe P.A. Fuchs E. J. Cell Biol. 1998; 143: 487-499Crossref PubMed Scopus (90) Google Scholar). Disruption of the keratin IF network in epidermal keratinocytes via the targeted expression of dominant-negative keratin mutants (17Vassar R. Coulombe P.A. Degenstein L. Albers K. Fuchs E. Cell. 1991; 64: 365-380Abstract Full Text PDF PubMed Scopus (330) Google Scholar, 18Coulombe P.A. Hutton M.E. Vassar R. Fuchs E. J. Cell Biol. 1991; 115: 1661-1674Crossref PubMed Scopus (165) Google Scholar, 19Takahashi K. Coulombe P.A. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 14776-14781Crossref PubMed Scopus (33) Google Scholar) or the introduction of null mutations (20Lloyd C., Yu, Q.C. Cheng J. Turksen K. Degenstein L. Hutton E. Fuchs E. J. Cell Biol. 1995; 129: 1329-1344Crossref PubMed Scopus (246) Google Scholar) results in lysis of the targeted cell population whenever the skin of such mice is subjected to trivial mechanical trauma. Mutations in keratin genes, weakening the structural framework of cells, increase the risk of cell rupture and cause a variety of human skin disorders (6Fuchs E. Cleveland D.W. Science. 1998; 279: 514-519Crossref PubMed Scopus (828) Google Scholar, 21Coulombe P.A. Curr. Opin. Cell Biol. 1993; 5: 17-29Crossref PubMed Scopus (95) Google Scholar).Keratins 8 and 18 (K8/18) are the major components of the IFs of simple or single-layered epithelia, as found in the gastrointestinal tract, liver, and exocrine pancreas, from which many carcinomas arise. Gene targeting techniques have been used to elucidate the function of K8/18. K8 knockout mice in one strain died around day 12 from undetermined tissue damage (22Baribault H. Price J. Miyai K. Oshima R.G. Genes Dev. 1993; 7: 1191-1202Crossref PubMed Scopus (218) Google Scholar), whereas in a different strain, they survived to adulthood, but colorectal hyperplasia and inflammation were present (23Baribault H. Penner J. Iozzo R.V. Wilson-Heiner M. Genes Dev. 1994; 8: 2964-2973Crossref PubMed Scopus (270) Google Scholar). K18 null mice were fertile and had a normal life span, whereas old K18 null mice developed a distinct liver pathology with abnormal hepatocytes containing K8-positive aggregates that resembled the Mallory bodies seen in human livers with alcoholic hepatitis (24Magin T.M. Schroder R. Leitgeb S. Wanninger F. Zatloukal K. Grund C. Melton D.W. J. Cell Biol. 1998; 140: 1441-1451Crossref PubMed Scopus (177) Google Scholar). Together with the report describing a mutation in the K18 gene in a patient with cryptogenic cirrhosis (25Ku N.O. Wright T.L. Terrault N.A. Gish R. Omary M.B. J. Clin. Invest. 1997; 99: 19-23Crossref PubMed Scopus (101) Google Scholar), additional work has indicated that K18 mutations may possibly cause or result in a predisposition to liver disease (26Omary M.B. Ku N.O. Hepatology. 1997; 25: 1043-1048Crossref PubMed Scopus (89) Google Scholar).Although the molecular basis for functions of K8/18 are unknown, dissection of interactions of K8/18 with associated proteins has provided clues to the physiological roles of K8/18. Several K8/18-associated proteins have been reported, including a protein kinase Cε-related kinase (27Omary M.B. Baxter G.T. Chou C.F. Riopel C.L. Lin W.Y. Strulovici B. J. Cell Biol. 1992; 117: 583-593Crossref PubMed Scopus (81) Google Scholar), an 85-kDa membrane-associated protein (28Chou C.F. Riopel C.L. Omary M.B. Biochem. J. 1994; 298: 457-463Crossref PubMed Scopus (21) Google Scholar), the stress-induced and constitutively expressed heat shock protein Hsp/c70 (29Napolitano E.W. Pachter J.S. Chin S.S. Liem R.K. J. Cell Biol. 1985; 101: 1323-1331Crossref PubMed Scopus (25) Google Scholar, 30Liao J. Lowthert L.A. Ghori N. Omary M.B. J. Biol. Chem. 1995; 270: 915-922Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar), the glucose-regulated protein Grp78 (31Liao J. Price D. Omary M.B. FEBS Lett. 1997; 417: 316-320Crossref PubMed Scopus (13) Google Scholar), and members of the 14-3-3 protein family (32Liao J. Omary M.B. J. Cell Biol. 1996; 133: 345-357Crossref PubMed Scopus (179) Google Scholar, 33Ku N.O. Liao J. Omary M.B. EMBO J. 1998; 17: 1892-1906Crossref PubMed Scopus (194) Google Scholar). In the present work, we screened a yeast two-hybrid library using K18 as a bait to search for new K18-associated proteins. Among the positive clones, we identified two identical ones encoding the C-terminal portion of human Mrj, a DnaJ/Hsp40 family protein. We report evidence for the in vivo association of Mrj with K18 and suggest a possible role of the Mrj-Hsp/c70 chaperone in the regulation of K8/18 filament organization.DISCUSSIONIn this study, we identified Mrj, a recently cloned DnaJ/Hsp40 family protein, as a K18-binding protein using the yeast two-hybrid system, biochemical analysis, and cell biological techniques. The human Mrj gene has been mapped to the chromosome 11q25 region, and the open reading frame of the gene encodes a protein of 242 amino acid residues containing a canonical J domain, a highly conserved 70-amino acid region at the N-terminal end of DnaJ/Hsp40 family proteins, and a glycine/phenylalanine-rich domain, which is also present in DnaJ/Hsp40 family proteins (Fig.1 A) (40Seki N. Hattori A. Hayashi A. Kozuma S. Miyajima N. Saito T. J. Hum. Genet. 1999; 44: 185-189Crossref PubMed Scopus (16) Google Scholar). Mouse homozygous Mrj mutants died at mid-gestation due to a failure of chorioallantoic fusion at embryonic day 8.5, of which the molecular mechanism is unknown (39Hunter P.J. Swanson B.J. Haendel M.A. Lyons G.E. Cross J.C. Development. 1999; 126: 1247-1258Crossref PubMed Google Scholar). We addressed that one of the specific functions of Mrj may be to regulate K8/18 filament organization.The DnaJ/Hsp40 family proteins work together with the DnaK/Hsp70 class of chaperones, which comprise a set of abundant cellular machines that assist a large variety of protein folding processes in almost all cellular compartments (43Hartl F.U. Nature. 1996; 381: 571-579Crossref PubMed Scopus (3090) Google Scholar, 44Bukau B. Horwich A.L. Cell. 1998; 92: 351-366Abstract Full Text Full Text PDF PubMed Scopus (2404) Google Scholar). The J domain of DnaJ/Hsp40 family proteins is essential to stimulate the weak intrinsic ATPase activity of Hsp70 proteins (43Hartl F.U. Nature. 1996; 381: 571-579Crossref PubMed Scopus (3090) Google Scholar, 44Bukau B. Horwich A.L. Cell. 1998; 92: 351-366Abstract Full Text Full Text PDF PubMed Scopus (2404) Google Scholar). Since Hsp70 proteins have a very broad substrate specificity (45Flynn G.C. Chappell T.G. Rothman J.E. Science. 1989; 245: 385-390Crossref PubMed Scopus (573) Google Scholar, 46Beckmann R.P. Mizzen L.E. Welch W.J. Science. 1990; 248: 850-854Crossref PubMed Scopus (1040) Google Scholar, 47James P. Pfund C. Craig E.A. Science. 1997; 275: 387-389Crossref PubMed Scopus (185) Google Scholar), it has been proposed that some of the DnaJ/Hsp40 family proteins act as specialized co-chaperones that recruit an Hsp70 protein to a specific set of substrates (48Cyr D.M. Langer T. Douglas M.G. Trends Biochem. Sci. 1994; 19: 176-181Abstract Full Text PDF PubMed Scopus (398) Google Scholar, 49Kelley W.L. Trends Biochem. Sci. 1998; 23: 222-227Abstract Full Text Full Text PDF PubMed Scopus (347) Google Scholar, 50Lu Z. Cyr D.M. J. Biol. Chem. 1998; 273: 27824-27830Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar). Cytosolic Hsp/c70 has been reported to be associated with K8/18 via direct binding to K8, although the nature of the relationship between Hsp/c70 and K8/18 remains uncertain (30Liao J. Lowthert L.A. Ghori N. Omary M.B. J. Biol. Chem. 1995; 270: 915-922Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar). We showed here that Mrj was associated in vitro with K8/18 filaments via direct binding to K18 using a co-sedimentation assay. In a two-hybrid assay, Mrj interacted strongly with K18, but not with other IF proteins, including K5, K8, K14, vimentin, GFAP, and desmin. Among the interactions between DnaJ/Hsp40 family proteins and various IF proteins that we have thus far tested using the two-hybrid method, only the Mrj-K18 interaction was apparently positive. Mrj was associated in vivo with K18 and Hsp/c70 and colocalized with K8/18 filaments. Mrj interacted with Hsc70 via its N terminus-containing J domain and bound to K18 through its C terminus. These results suggest that Mrj may act as a K18 (K8/18)-specific adaptor protein to link K18 (K8/18) to the Hsp/c70 chaperone. Furthermore, microinjection of anti-Mrj antibody resulted in the disorganization of K8/18 filaments, indicating that Mrj plays an indispensable role in the organization of K8/18 filaments in vivo.In HeLa cells, the overexpression of the N-terminal region of Mrj (Myc-Mrj-N2) resulted in the disruption not only of K8/18 filaments, but also of actin filaments, microtubules, and vimentin filaments. Because Mrj-N2 can interact with Hsc70, but not with K18, the overexpressed Myc-Mrj-N2 protein would be initially expected to dominant-negatively inhibit the specific interaction between endogenous Mrj and Hsp/c70. As described above, Michels et al. (42Michels A.A. Kanon B. Bensaude O. Kampinga H. J. Biol. Chem. 1999; 274: 36757-36763Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar) recently reported that the overexpression of a truncated protein restricted to the J domain of Hsp40 showed dominant-negative effects on the chaperone activity of Hsp70 in a living cell. Therefore, the effects of the overexpression of Myc-Mrj-N2 on major cytoskeletal systems observed in this study might be caused by the disturbance of some or overall functions of the Hsp/c70 chaperone system rather than by the specific inhibition of the Mrj-Hsp/c70 interaction. If this is the case, these results indicate a possibility that Hsp/c70 chaperones may play an important role in the regulation of the organization of actin filaments, microtubules, and vimentin filaments as well as K8/18 filaments. In addition, it is tempting to speculate that there may exist some specific DnaJ/Hsp40 family proteins that link actin, tubulin, or various IF proteins to Hsp/c70 (Fig.7). In support of this idea, there is a growing body of evidence suggesting an intimate relationship between the cytoskeleton and molecular chaperones, including the Hsp/c70 family (51Liang P. MacRae T.H. J. Cell Sci. 1997; 110: 1431-1440Crossref PubMed Google Scholar). In S. cerevisiae, it was genetically demonstrated that Ssa1p (yeast cytosolic Hsp70) and Ydj1p (yeast cytosolic DnaJ homologue) play a role in the regulation of microtubule formation (52Oka M. Nakai M. Endo T. Lim C.R. Kimata Y. Kohno K. J. Biol. Chem. 1998; 273: 29727-29737Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar). It was also reported that in human gastric cancer cells, overexpressed BAG-1, a negative regulator of Hsp/c70 chaperone activity, colocalizes with keratin filaments as well as actin filaments and promoted cell migration (53Naishiro Y. Adachi M. Okuda H. Yawata A. Mitaka T. Takayama S. Reed J.C. Hinoda Y. Imai K. Oncogene. 1999; 18: 3244-3251Crossref PubMed Scopus (48) Google Scholar). Taken together, these observations will shed new light on a possible role of the Hsp/c70 chaperone in the regulation of cytoskeletons.αB-crystallin and Hsp27, members of the small Hsp family, were reported to be associated with both soluble and filamentous IF proteins, including GFAP, vimentin, and keratin (54Nicholl I.D. Quinlan R.A. EMBO J. 1994; 13: 945-953Crossref PubMed Scopus (394) Google Scholar, 55Perng M.D. Cairns L. van den IJssel P. Prescott A. Hutcheson A.M. Quinlan R.A. J. Cell Sci. 1999; 112: 2099-2112Crossref PubMed Google Scholar). The in vitro polymerization of GFAP and vimentin is repressed by αB-crystallin (54Nicholl I.D. Quinlan R.A. EMBO J. 1994; 13: 945-953Crossref PubMed Scopus (394) Google Scholar) as well as by Hsp27 (55Perng M.D. Cairns L. van den IJssel P. Prescott A. Hutcheson A.M. Quinlan R.A. J. Cell Sci. 1999; 112: 2099-2112Crossref PubMed Google Scholar). A physiological role for αB-crystallin with IFs was further demonstrated by a recent report describing that a mutation in the αB-crystallin gene causes desmin aggregation in certain myopathies called desmin-related myopathies (56Vicart P. Caron A. Guicheney P. Li Z. Prevost M.C. Faure A. Chateau D. Chapon F. Tome F. Dupret J.M. Paulin D. Fardeau M. Nat. Genet. 1998; 20: 92-95Crossref PubMed Scopus (962) Google Scholar). As for the pathological aggregation of K8/18, it is well known that Mallory bodies in the livers of human patients with alcoholic hepatitis and of griseofulvin-treated mice are the cytoplasmic accumulation of K8/18-containing aggregates (57Denk H. Gschnait F. Wolff K. Lab. Invest. 1975; 32: 773-776PubMed Google Scholar, 58Franke W.W. Denk H. Schmid E. Osborn M. Weber K. Lab. Invest. 1979; 40: 207-220PubMed Google Scholar, 59Jensen K. Gluud C. Hepatology. 1994; 20: 1330-1342Crossref PubMed Scopus (44) Google Scholar, 60Jensen K. Gluud C. Hepatology. 1994; 20: 1061-1077Crossref PubMed Scopus (76) Google Scholar). As described earlier, old K18 null mice developed a distinctive liver pathology with abnormal hepatocytes containing K8-positive aggregates that resembled Mallory bodies (24Magin T.M. Schroder R. Leitgeb S. Wanninger F. Zatloukal K. Grund C. Melton D.W. J. Cell Biol. 1998; 140: 1441-1451Crossref PubMed Scopus (177) Google Scholar). The finding that K8/18 filament organization may be regulated by the Mrj-Hsp/c70 chaperone will provide a new clue to dissect the mechanism of the formation of Mallory bodies.Assembly and disassembly of IF organization are regulated by the site-specific phosphorylation state of IFs, and these phosphorylations are spatially and temporally regulated during cellular events, including mitosis (9Inagaki M. Matsuoka Y. Tsujimura K. Ando S. Tokui T. Takahashi T. Inagaki N. Bioessays. 1996; 18: 481-487Crossref Scopus (160) Google Scholar, 10Inagaki M. Nishi Y. Nishizawa K. Matsuyama M. Sato C. Nature. 1987; 328: 649-652Crossref PubMed Scopus (334) Google Scholar, 11Eriksson J.E. Opal P. Goldman R.D. Curr. Opin. Cell Biol. 1992; 4: 99-104Crossref PubMed Scopus (126) Google Scholar, 61Yasui Y. Amano M. Nagata K. Inagaki N. Nakamura H. Saya H. Kaibuchi K. Inagaki M. J. Cell Biol. 1998; 143: 1249-1258Crossref PubMed Scopus (148) Google Scholar). When phosphorylated by purified protein kinase C, calmodulin-dependent protein kinase, or cAMP-dependent kinase, K8/18 filaments reconstituted in vitro undergo complete disassembly, and there is a significant release of soluble K8 and K18 proteins from the keratin filaments (12Yano T. Tokui T. Nishi Y. Nishizawa K. Shibata M. Kikuchi K. Tsuiki S. Yamauchi T. Inagaki M. Eur. J. Biochem. 1991; 197: 281-290Crossref PubMed Scopus (80) Google Scholar). It has been reported that the increase in K8/18 phosphorylation is associated with the binding of the soluble fraction of K8/18 to 14-3-3 proteins (33Ku N.O. Liao J. Omary M.B. EMBO J. 1998; 17: 1892-1906Crossref PubMed Scopus (194) Google Scholar). Because Mrj is associated with both soluble and filamentous K8/18, it is likely that the phosphorylation state of K8/18 may not directly affect the association of Mrj with K8/18. The relationship between the phosphorylation-dependent and Mrj-dependent regulation of K8/18 filaments needs to be investigated in the future.In conclusion, we are the first to report that human Mrj proteins directly interact with K18 and might regulate K8/18 filament organization as K18-specific co-chaperones working together with Hsp/c70. These observations will pave the way toward further research on K8/18 filament organization as well as understanding the pathological mechanisms of Mallory body formation. Intermediate filaments (IFs)1 are major components of the cytoskeleton and nuclear envelope in most types of eukaryotic cells (1Lazarides E. Nature. 1980; 283: 249-256Crossref PubMed Scopus (1433) Google Scholar, 2Franke W.W. Cell. 1987; 48: 3-4Abstract Full Text PDF PubMed Scopus (160) Google Scholar, 3Steinert P.M. Liem R.K. Cell. 1990; 60: 521-523Abstract Full Text PDF PubMed Scopus (140) Google Scholar, 4Skalli O. Goldman R.D. Cell Motil. Cytoskeleton. 1991; 19: 67-79Crossref PubMed Scopus (136) Google Scholar, 5Fuchs E. Weber K. Annu. Rev. Biochem. 1994; 63: 345-382Crossref PubMed Scopus (1272) Google Scholar, 6Fuchs E. Cleveland D.W. Science. 1998; 279: 514-519Crossref PubMed Scopus (828) Google Scholar). Although structural components of other major cytoskeletal proteins (actin and tubulin) are highly conserved in different cell types, the constituent proteins of IFs show intriguing molecular diversities and are expressed in tissue-specific programs, which makes them ideal molecular markers for the differentiation state in developmental biology and pathology (7Steinert P.M. Roop D.R. Annu. Rev. Biochem. 1988; 57: 593-625Crossref PubMed Scopus (1119) Google Scholar). Cytoplasmic IFs are usually organized into 10-nm diameter fibers that are prevalent in the perinuclear region, where they appear to be attached to the outer nuclear envelope membrane or to nuclear pore complexes (4Skalli O. Goldman R.D. Cell Motil. Cytoskeleton. 1991; 19: 67-79Crossref PubMed Scopus (136) Google Scholar). Continuous with this perinuclear array, IFs extend radially through the cytoplasm, eventually forming a close association with the plasma membrane. The intracellular IF networks were thought to be relatively stable in comparison with other cytoskeletal components such as actin filaments and microtubules; however, IFs have dynamic properties (8Inagaki M. Nakamura Y. Takeda M. Nishimura T. Inagaki N. Brain Pathol. 1994; 4: 239-243Crossref PubMed Scopus (124) Google Scholar, 9Inagaki M. Matsuoka Y. Tsujimura K. Ando S. Tokui T. Takahashi T. Inagaki N. Bioessays. 1996; 18: 481-487Crossref Scopus (160) Google Scholar). Accumulating data strongly suggest that assembly and disassembly of IF organization are regulated by the site-specific phosphorylation state of IFs (9Inagaki M. Matsuoka Y. Tsujimura K. Ando S. Tokui T. Takahashi T. Inagaki N. Bioessays. 1996; 18: 481-487Crossref Scopus (160) Google Scholar, 10Inagaki M. Nishi Y. Nishizawa K. Matsuyama M. Sato C. Nature. 1987; 328: 649-652Crossref PubMed Scopus (334) Google Scholar, 11Eriksson J.E. Opal P. Goldman R.D. Curr. Opin. Cell Biol. 1992; 4: 99-104Crossref PubMed Scopus (126) Google Scholar), which is determined by kinase/phosphatase equilibria (11Eriksson J.E. Opal P. Goldman R.D. Curr. Opin. Cell Biol. 1992; 4: 99-104Crossref PubMed Scopus (126) Google Scholar, 12Yano T. Tokui T. Nishi Y. Nishizawa K. Shibata M. Kikuchi K. Tsuiki S. Yamauchi T. Inagaki M. Eur. J. Biochem. 1991; 197: 281-290Crossref PubMed Scopus (80) Google Scholar, 13Toivola D.M. Goldman R.D. Garrod D.R. Eriksson J.E. J. Cell Sci. 1997; 110: 23-33Crossref PubMed Google Scholar, 14Inada H. Togashi H. Nakamura Y. Kaibuchi K. Nagata K. Inagaki M. J. Biol. Chem. 1999; 274: 34932-34939Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar). The keratin subfamily, which is preferentially expressed in epithelial cells, has over 20 members (keratins 1–20) that form obligate noncovalent heteropolymers of at least one type I keratin (keratins 9–20) and one type II keratin (keratins 1–8) (15Moll R. Franke W.W. Schiller D.L. Geiger B. Krepler R. Cell. 1982; 31: 11-24Abstract Full Text PDF PubMed Scopus (4495) Google Scholar). In epithelial cells, keratin filaments are typically organized in a cytoplasmic reticular network of anastomosing filament bundles involving their noncovalent linkage at the surface of the nucleus and at cell adhesion complexes. This adhesion machinery consists of desmosomes, which mediate adhesion between cells, and hemidesmosomes, which mediate the adhesion of epithelial cells to the underlying basal lamina. One role that has been ascribed to various keratin filament networks of stratified squamous epithelia is to impart mechanical integrity to cells, without which the cells become fragile and prone to rupture (16Hutton E. Paladini R.D., Yu, Q.C. Yen M. Coulombe P.A. Fuchs E. J. Cell Biol. 1998; 143: 487-499Crossref PubMed Scopus (90) Google Scholar). Disruption of the keratin IF network in epidermal keratinocytes via the targeted expression of dominant-negative keratin mutants (17Vassar R. Coulombe P.A. Degenstein L. Albers K. Fuchs E. Cell. 1991; 64: 365-380Abstract Full Text PDF PubMed Scopus (330) Google Scholar, 18Coulombe P.A. Hutton M.E. Vassar R. Fuchs E. J. Cell Biol. 1991; 115: 1661-1674Crossref PubMed Scopus (165) Google Scholar, 19Takahashi K. Coulombe P.A. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 14776-14781Crossref PubMed Scopus (33) Google Scholar) or the introduction of null mutations (20Lloyd C., Yu, Q.C. Cheng J. Turksen K. Degenstein L. Hutton E. Fuchs E. J. Cell Biol. 1995; 129: 1329-1344Crossref PubMed Scopus (246) Google Scholar) results in lysis of the targeted cell population whenever the skin of such mice is subjected to trivial mechanical trauma. Mutations in keratin genes, weakening the structural framework of cells, increase the risk of cell rupture and cause a variety of human skin disorders (6Fuchs E. Cleveland D.W. Science. 1998; 279: 514-519Crossref PubMed Scopus (828) Google Scholar, 21Coulombe P.A. Curr. Opin. Cell Biol. 1993; 5: 17-29Crossref PubMed Scopus (95) Google Scholar). Keratins 8 and 18 (K8/18) are the major components of the IFs of simple or single-layered epithelia, as found in the gastrointestinal tract, liver, and exocrine pancreas, from which many carcinomas arise. Gene targeting techniques have been used to elucidate the function of K8/18. K8 knockout mice in one strain died around day 12 from undetermined tissue damage (22Baribault H. Price J. Miyai K. Oshima R.G. 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