Mixed Lineage Kinases

A New Family of Protein Kinases Containing a Double Leucine Zipper Domain, a Basic Motif and a SH3 Domain
  • Donna S. Dorow
  • Lisa Devereux
  • Richard J. Simpson


Protein kinases play critical roles in the regulation of cellular processes. They control many of the pathways leading to the biochemical and morphological changes associated with cellular growth and division (Dunphy and Newport, 1988; Morgan et al, 1989). They also serve as growth factor receptors and signal transducers and have been implicated in cellular transformation and malignancy (reviewed by Hunter and Karin, 1992; Posada and Cooper, 1992; Birchmeier et al, 1993).


Catalytic Domain Leucine Zipper Charged Residue Basic Domain Kinase Catalytic Domain 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Anderson, D., Koch, C.A., Grey, L., Ellis, C., Moran, M. and Pawson, T. (1990). Binding of SH2 domains of phospholipase C 1, GAP, and Src to activated growth factor receptors. Science 250, 979–982.Google Scholar
  2. Atkinson, R.A., Saudek, V., Huggins, J.P. and Pelton, J.T. (1991). 1H NMR and circular dichroism studies of the N-terminal domain cyclic GMP dependent protein kinase: a leucine/isoleucine zipper. Biochem- istry 30, 9387–9395.Google Scholar
  3. Barton, D.E., Foellmer, B.E., Du, J., Tamm, J., and Derynck, R. (1988). Chromosomal mapping of genes for transforming growth factors beta 2 and beta 3 in man and mouse: dispersion of the TGF-beta gene family. Oncogene Res. 3, 323–331.PubMedGoogle Scholar
  4. Ben-David, Y., Letwin, K., Tannok, L., Bernstein, A. and Pawson, T. (1991). A mammalian protein kinase with potential for serine/threonine and tyrosine phosphorylation is related to the cell cycle regulators. EMBO J. 10, 317–325.Google Scholar
  5. Birchmeier, C., Sonnenberg, E., Weidner, K.M. and Walter, B. (1993) Tyrosine kinase receptors in the control of epithelial growth and morphogenesis during development. BioEssays 15, 185–189.Google Scholar
  6. Booker, G.W., Gout, I., Downing, A.K., Driscoll, P.C., Boyd, J., Waterfield, M.D. and Campbell, I.D. (1993). Solution structure and ligand-binding site of the SH3 domain of the p85a subunit of phosphatidylinositol 3-kinase. Cell 73, 813–822.PubMedCrossRefGoogle Scholar
  7. Cantley, L.C., Auger, K.R., Carpenter, C., Duckworth, B., Graziani, A., Kapeller, R. and Soltoff, S. (1991). Oncogenes and signal transduction. Cell 64, 281–302.PubMedCrossRefGoogle Scholar
  8. Choo, K.H., Brown, R.M. and Earle, E. (1990) In situ hybridization of chromosomes. In: Protocols in Human Molecular Genetics, Vol 7, Ed. C.Matthews. Humana Press, USA.Google Scholar
  9. Chou, P.Y. and Fasman, G.D. (1978). Empirical predictions of protein conformation. Ann. Rev. Biochem. 47, 251–276.Google Scholar
  10. Dorow, D.S., Devereux, L., Dietzsch, E. and deKretser, T. (1993). Identification of a new family of human epithelial protein kinases containing two leucine/isoleucine zipper domains. Eur J Biochem 231. 701–710.CrossRefGoogle Scholar
  11. Dunphy, W.G. and Newport, J.W. (1988). Unravelling of mitotic control mechanisms. Cell 55, 925–928.PubMedCrossRefGoogle Scholar
  12. Eck, M.J., Atwell, S.K., Shoelson, S.E. and Harrison, S.C. (1994) Structure of the regulatory domains of the Src-family tyrosine kinase Lck. Nature 368, 764–769.PubMedCrossRefGoogle Scholar
  13. Egan, S.E., Giddings, B.W., Brooks, M.W., Buday, L., Sizeland, A.M., and Weinberg, R.A. (1993). Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation. Nature 363, 45–51.PubMedCrossRefGoogle Scholar
  14. Ekstrand, A.J. and Zech, L. (1987). Human c-fos proto-oncogene mapped to chromosome 14 band g24.3–31. Possibilities for oncogene activation by chromosomal rearrangements in human neoplasms. Exp Cell Res 169, 262–266.Google Scholar
  15. Ezoe, K., Lee, S-t., Strunk, K. and Spritz, R.A. (1994). PTK1, a novel protein kinase required for proliferation of human melanocytes. Oncogene 9, 935–938.PubMedGoogle Scholar
  16. Featherstone, C. and Russell, P. (1991). Fission yeast P107wee1 mitotic inhibitor is a tyrosine/serine kinase. Nature 349, 808–811.PubMedCrossRefGoogle Scholar
  17. Gallo, K.A., Mark, M.R., Scadden, D.T., Wang, Z., Gu, Q. and Godwoski, P.J. (1994) Identification and characterization of SPRK, a novel src-homology 3 domain-containing proline-rich kinase with serine/threonine kinase activity. J Biol Chem 269, 15092–15100.PubMedGoogle Scholar
  18. Gout, I., Dhand, R., Hiles, I.D., Fry, M.J., Panayotou, G., Das, P., Truong, O., Totty, N.F., Hsuan, J., Booker, G.W., Campbell, I.D. and Waterfield, M.D. (1993). The GTPase dynamin binds to and is activated by a subset of SH3 domains. Cell 75, 25–36.PubMedGoogle Scholar
  19. Hanks, S.K., Quinn, A M. and Hunter, T. (1988). The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science 241, 42–52.PubMedCrossRefGoogle Scholar
  20. Hanks, S.K. (1991). Eukaryotic protein kinases. Current Opinion in Structural Biology 1, 369–383CrossRefGoogle Scholar
  21. Harrison, G.S., Drabkin, H.A., Kao, F.T., Hartz, J., Chu, E.H., Wu, B.J. and Morimoto, R.I. (1987). Chromosomal location of human genes encoding major heat-shock protein HSP70. Somat. Cell Mol. Genet. 13, 119–130.Google Scholar
  22. Higgins, D.G. and Sharp, P.M. (1988). Clustal: a package for performing multiple sequence alignments on a microcomputer. Gene 73, 237–244.PubMedCrossRefGoogle Scholar
  23. Hunter, T. (1991). Protein kinase classification. Methods Enzymol 200, 3–37.PubMedCrossRefGoogle Scholar
  24. Hunter, T. and Karin, M. (1992). The regulation of transcription by phosphorylation. Cell 70, 375–387.PubMedCrossRefGoogle Scholar
  25. Ing, Y.L., Leung, I.W.L., Heng, H.H.Q., Tsui, L-C., Lassam, N.J. (1994). MLK-3: identification of a widely-ex- pressed protein kinase bearing an SH3 and leucine zipper-basic region domain. Oncogene 9, 1745–1750.PubMedGoogle Scholar
  26. Kalderon, D., Richardson, W.D., Markham, A T. and Smith, A.E. (1984). Sequence requirements for nuclear localization of simian virus large-T antigen. Nature 311, 33–38.PubMedCrossRefGoogle Scholar
  27. Khoda, D., Hatanaka, H., Odaka, M, Mandiyan, V., Ullrich, A., Schlessinger, J and Inagaki, F. (1993). Solution structure of the SH3 domain of phospholipase C-y. Cell 72, 953–960.CrossRefGoogle Scholar
  28. Koch, C.A., Anderson, D., Moran, M.F., Ellis, C. and Pawson, T. (1991). SH2 and SH3 domains: Elements that control interactions of cytoplasmic signalling proteins. Science 252, 668–674.Google Scholar
  29. Koyama, S., Yu, H., Dalgarno, D.C., Shin, T.B., Zydowsky, L.D. and Schreiber, S.L. (1993). Structure of the PI3K SH3 domain and analysis of the SH3 family. Cell 72, 945–952.PubMedCrossRefGoogle Scholar
  30. Landgraf, W., Hofmann, F., Pelton, J.T. and Huggins, J.P. (1990). Effects of cyclic GMP on the secondary structure of cyclic GMP dependent protein kinase and analysis of the enzyme’s amino-terminal domain by far-ultraviolet circular dichroism. Biochemistry 29, 9921–9928.PubMedCrossRefGoogle Scholar
  31. Landschultz, W.H., Johnson, P.F. and McKnight, S.L. (1988). The leucine zipper: a hypothetical structure common to a new class of DNA binding proteins. Science 240, 1759–1764.CrossRefGoogle Scholar
  32. Lowenstein, E.J., Daly, R.J., Batzer, A.G., Li, W., Margolis, B., Lammers, R., Ullrich, A., and Schlessinger, J. (1992). The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Cell 70, 431–442.PubMedCrossRefGoogle Scholar
  33. Mayer, B.J., Hamaguchi, M. and Hanafusa, H. (1988). A novel viral oncogene with structural similarity to phospholipase C. Nature 332, 272–275.PubMedCrossRefGoogle Scholar
  34. Mayer, B.J., Jackson, P.K., and Baltimore, D. (1991). The noncatalytic src homology region 2 segment of abl tyrosine kinase binds to tyrosine-phosphorylated cellularproteins with high affinity. Proc. Natl. Acad. Sci. ( USA ) 88, 627–631.Google Scholar
  35. McKnight, S.L. (1991). Molecular zippers in gene regulation. Scientific American 4, 32–39.Google Scholar
  36. Morgan, D., Kaplan, J.M, Bishop, J.M. and Varmus, H.A. (1989). Mitosis-specific phosphorylation of p60c-“c by p34cdc2-associated protein kinase. Cell 57, 775–786.PubMedCrossRefGoogle Scholar
  37. Murre, C., McCaw, P.S. and Baltimore, D. (1989). A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, MyoD, and myc proteins. Cell 56, 777–783.PubMedCrossRefGoogle Scholar
  38. Musacchio, A., Noble, M., Pauptit, R., Wierenga, R and Saraste, M. (1992). Crystal structure of a Src-homology 3 (SH3) domain. Nature 359, 851–855.PubMedCrossRefGoogle Scholar
  39. Noble, M.E.M., Musacchio, A., Saraste, M., Courtneige, S.A. and Wierenga, R.K. (1993). Crystal structure of the SH3 domain in human Fyn; comparison of the three-dimensional structures of SH3 domains in tyrosine kinases and spectrin. EMBO J. 12, 2617–2624.Google Scholar
  40. O’Shea, E.K., Klemm, J.D., Kim, P.S. and Alber, T. (1991). X-ray structure of the GCN4 leucine zipper, a two-stranded, parallel coiled coil. Science 254, 539–544.PubMedCrossRefGoogle Scholar
  41. Pawson, T. and Gish, G.D. (1992). SH2 and SH3 domains: from structure to function. Cell 71, 359–362. Posada, J., and Cooper, J.A. (1992). Molecular signal integration. Interplay between serine, threonine, and tyrosine phosphorylation. Mol. Biol. Cell. 3, 583–592.Google Scholar
  42. Ren, R., Mayer, B.J., Cicchetti, P., Baltimore, D. (1993). Identification of a ten-amino acid proline-rich SH3 binding site. Science 259, 1157–1161.PubMedCrossRefGoogle Scholar
  43. Rodaway, A.R.F., Sternberg, M.J.E., and Bentley, D.L. (1989). Similarity in membrane proteins. Nature 342, 624. Schiffer, M. and Edmundson, A.B.(1967). The use of helical wheels to represent the structures of proteins and to identify segments with helical potential. Biophysical J. 7, 121–135.Google Scholar
  44. Stern, D.F., Zheng, P., Beider, D.R. and Zerillo, C. (1991). Spkl, a new kinase from Saccharomyces cerevisiae, phosphorylates proteins on serine, threonine and tyrosine. Mol. Cell. Biol. 11, 987–1001.Google Scholar
  45. Testa, J.R. (1990). Chromosome translocations in human cancer. Cell Growth Differ. 1, 97–101.PubMedGoogle Scholar
  46. Vinson, C.R., Sigler, P.B. and McKnight, S.L. (1989). Scissors-grip model for DNA recognition by a family of leucine zipper proteins. Science 246, 911–916.PubMedCrossRefGoogle Scholar
  47. Yu, H., Rosen, M., Shin, T.B., Seidell-Dugan, C., Brugge, J.S. and Schreiber, S.L. (1992). Solution structure of the SH3 domain of src and identification of it’s ligand binding site. Science 258, 1665–1668.PubMedCrossRefGoogle Scholar
  48. Yu, H. Chen, J.K., Feng, S., Dalgarno, D.C., Brauer, A.W. and Schreiber, S.L. (1994) Structural basis of binding of proline-rich peptidees to SH3 domains. Cell 76, 933–945.Google Scholar

Copyright information

© Springer Science+Business Media New York 1995

Authors and Affiliations

  • Donna S. Dorow
    • 1
  • Lisa Devereux
    • 1
  • Richard J. Simpson
    • 2
  1. 1.Research DivisionThe Peter MacCallum Cancer InstituteMelbourneAustralia
  2. 2.The Joint Protein Structure LaboratoryLudwig Institute for Cancer Research (Melbourne Branch) and The Walter and Eliza Hall Institute for Medical ResearchParkvilleAustralia

Personalised recommendations