UC San Diego SearchMenu

Cell cycle regulation

Kun Ping Lu

Appointment Period: 1993-1994 / Grant Year: [09]

Kun Ping LuThe NIMA kinase is essential for progression through mitosis in Aspergillus nidulans. To examine whether there is a NIMA-like pathway in other eukaryotic cell cycles, we expressed NIMA and its dominant negative mutants in two different eukaryotic systems. In Xenopus oocytes, NIMA induced germinal vesicle breakdown without activating Mos, CDC2, or MAP kinase. In HeLa cells, NIMA induced premature mitotic events without activating CDC2, whereas the mutants caused a specific G2 arrest but did not block mutant CDC2T14AY15F-induced premature entry into mitosis. A sequence essential for both these phenotypes was mapped to a region of approximately 100 amino acids lying just after the catalytic domain of NIMA that shows a significant similarity to protein interaction domains in other proteins. These results provide evidence for the existence of a NIMA-like mitotic pathway in vertebrate cells.

More recently, we investigated the interaction between the NIMA kinase and the human protein Pin1, a peptidyl-prolyl cis/trans isomerase (PPIase). PPIases are important in protein folding, assembly and/or transport, but none has so far been shown to be required for cell viability. Pin1 is nuclear PPIase containing a WW protein interaction domain, and is structurally and functionally related to Ess1/Ptf1, an essential protein in budding yeast. PPIase activity is necessary for Ess1/Pin1 function in yeast. Depletion of Pin1/Ess1 from yeast or HeLa cells induces mitotic arrest, whereas HeLa cells overexpressing Pin1 arrest in the G2 phase of the cell cycle. Pin1 is thus an essential PPIase that regulates mitosis presumably by interacting with NIMA and attenuating its mitosis-promoting activity.

PUBLICATIONS (resulting from this training, and some recent ones)

Lu KP, Hunter T. (1995) The NIMA kinase: a mitotic regulator in Aspergillus nidulans and vertebrate cells. Prog Cell Cycle Res. 1:187-205.

Lu KP, Hunter T. (1995) Evidence for a NIMA-like mitotic pathway in vertebrate cells. Cell 81:413-24.

Lu KP, Hanes SD, Hunter T. (1996) A human peptidyl-prolyl isomerase essential for regulation of mitosis. Nature 380:544-7.

Songyang Z, Lu KP, Kwon YT, Tsai LH, Filhol O, Cochet C, Brickey DA, Soderling TR, Bartleson C, Graves DJ, DeMaggio AJ, Hoekstra MF, Blenis J, Hunter T, Cantley LC. (1996) A structural basis for substrate specificities of protein Ser/Thr kinases: primary sequence preference of casein kinases I and II, NIMA, phosphorylase kinase, calmodulin-dependent kinase II, CDK5, and Erk1. Mol Cell Biol. 16:6486-93.

Ranganathan R, Lu KP, Hunter T, Noel JP. (1997) Structural and functional analysis of the mitotic rotamase Pin1 suggests substrate recognition is phosphorylation dependent. Cell 89:875-86.

Shen M, Haggblom C, Vogt M, Hunter T, Lu KP. (1997) Characterization and cell cycle regulation of the related human telomeric proteins Pin2 and TRF1 suggest a role in mitosis. Proc Natl Acad Sci USA 94:13618-23.

Verdecia MA, Bowman ME, Lu KP, Hunter T, Noel JP. (2000) Structural basis for phosphoserine-proline recognition by group IV WW domains. Nat Struct Biol. 7:639-43.

Liou YC, Ryo A, Huang HK, Lu PJ, Bronson R, Fujimori F, Uchida T, Hunter T, Lu KP. (2002) Loss of Pin1 function in the mouse causes phenotypes resembling cyclin D1-null phenotypes. Proc Natl Acad Sci USA 99:1335-40.

Liou YC, Sun A, Ryo A, Zhou XZ, Yu ZX, Huang HK, Uchida T, Bronson R, Bing G, Li X, Hunter T, Lu KP. (2003) Role of the prolyl isomerase Pin1 in protecting against age-dependent neurodegeneration. Nature 424:556-61.

Wulf, G., Garg, P., Liou, Y. Y., Iglehart, D. and Lu, K. P. (2004) Modeling breast cancer in vivo and ex vivo uncovers an essential role for Pin1 in tumorigenesis. EMBO J. 23:3397-3407.

Suizu, F., Ryo, A., Wulf, G., and Lu, K. P. (2006) Pin1 regulates centrosome duplication and its overexpression induces centrosome amplification, chromosome instability and oncogenesis. Mol Cell Biol. 26:1463-1479.

Pastorino, L., Sun, A., Lu, P. J., Zhou, X. Z., Balastik, M., Finn, G., Wulf, G., Lim, J., Li, S. H., Li, X., Xia, W., Nicholson, L. and Lu, K. P. (2006) The prolyl isomerase Pin1 regulates amyloid precursor protein processing and Amyloid-beta production. Nature 440: 528-534.