| The
research in our laboratory is centered on two cellular processes
that are of fundamental importance in the eukaryotic cell cycle
- chromosome segregation
(or mitosis) and cellular morphogenesis (or spatial control of cell growth
and division). To ensure the proliferation of progeny cells that have identical
genetic contents, these two processes must be properly controlled and tightly
coordinated. Errors in these processes are common causes of many forms
of human disease. The organism that we have chosen to use for our studies
is the budding yeast Saccharomyces cerevisiae, which is amenable to the sophisticated
genetic, genomic, biochemical, cytological and molecular methodologies that
we use.
Chromosome Segregation
During chromosome segregation, the kinetochore of each chromosome must attach
to microtubules. Furthermore, each of the two kinetochores of a chromosome
pair (sister chromatids) must attach to microtubules that emanate from a single
pole of the mitotic spindle and the two sister kinetochores must attach to
microtubules from opposite poles. This pattern of bipolar attachment
allows the sister chromatids to separate and move subsequently towards opposite
poles. How kinetochore-microtubule attachment is regulated is very poorly
understood. Through the study of mutant yeast cells that fail to segregate
chromosomes properly (see figure), we have identified the Ipl1/Sli15/Bir1 protein
kinase complex as a central regulator of kinetochore-microtubule attachment. Sister
kinetochores of yeast cells that are defective in this complex often attach
to microtubules from the same pole. The genes encoding human homologs
of proteins in this complex (Aurora/INCENP/Survivin) are deregulated in diverse
forms of human cancer.
To understand how the Ipl1 kinase complex regulates kinetochore-microtubule
attachment, we have identified and studied a number of physiological substrates
of this complex. These
substrates include kinetochore proteins (e.g., the Dam1 complex) and proteins
that affect microtubule function. Amazingly, many of these yeast proteins also
have human counterparts that are deregulated in diverse forms of human cancer. Thus,
it is clear that our studies not only help us understand chromosome segregation
in yeast (and humans) but also may help us understand the connection between
chromosome missegregation and human tumorigenesis. Our current studies
are focused on understanding at the molecular level how the phosphorylation of
specific proteins by the Ipl1 kinase complex affects the chromosome segregation
process.
Cellular Morphogenesis
In most eukaryotic cells, polarized cell growth requires the proper
localization (to specific sites on the plasma membrane) of the
evolutionarily conserved Cdc42 GTP-binding protein. This
protein functions as a molecular switch (through the conversion
between the GTP- and GDP-bound forms) in signal transduction pathways
that regulate the polarized organization of the actin cytoskeleton
and thus the spatial pattern and site of cell growth. Through
the study of mutant yeast cells that are defective in cellular
morphogenesis, we have identified and characterized several proteins
that regulate the conversion between GTP- and GDP-bound forms of
Cdc42.
To understand how Cdc42 organizes the actin cytoskeleton, we have
identified the structurally related Gic1 and Gic2 proteins as effector
proteins that associate with GTP-bound Cdc42 at sites of active cell
growth (see figure). At these sites, Gic1 and Gic2 associate
with additional proteins, many of which are known to be involved
in polarized cell growth and division. We are currently studying
at the molecular level how Gic1/Gic2 and other proteins function
with Cdc42 to regulate the actin cytoskeleton and thus polarized
cell growth |
Selected Publications
Kenneth R. Henry, Kathleen D'Hondt, Ji Suk Chang, David A. Nix, M. Jamie T.V.
Cope, Clarence S.M. Chan, David G. Drubin, and Sandra K. Lemmon (2003) The Actin-Regulating
Kinase Prk1p Negatively Regulates Scd5p, a Suppressor of Clathrin Deficiency,
in Actin Organization and Endocytosis. Current Biology 13: 1564-1569
Mehta S, Yang XM, Chan CS, Dobson MJ, Jayaram M, Velmurugan S. (2002) The 2 micron
plasmid purloins the yeast cohesin complex: a mechanism for coupling plasmid
partitioning and chromosome segregation? The Journal of Cell Biology 158: 625-37
Phospho-Regulation of Kinetochore-Microtubule Attachments by
the Aurora Kinase Ipl1p
Iain M. Cheeseman, Scott Anderson, Miri Jwa, Erin M. Green, Jung-seog Kang,
John R. Yates III, Clarence S.M. Chan, David G. Drubin, and Georjana Barnes
Cell 111(2002): 163-172
Kang J, Cheeseman IM, Kallstrom G, Velmurugan S, Barnes G, Chan CS.(2001) Functional
cooperation of Dam1, Ipl1, and the inner centromere protein (INCENP)-related
protein Sli15 during chromosome segregation. The Journal of Cell Biology 155:
763-74
Drees BL, Sundin B, Brazeau E, Caviston JP, Chen GC, Guo W, Kozminski KG, Lau
MW, Moskow JJ, Tong A, Schenkman LR, McKenzie A 3rd, Brennwald P, Longtine
M, Bi E, Chan C, Novick P, Boone C, Pringle JR, Davis TN, Fields S, Drubin
DG (2001)
A
protein
interaction map for cell polarity development. The Journal of Cell Biology
154(3):549-71
Bi E, Chiavetta JB, Chen H, Chen GC, Chan CS, Pringle J (2000) Identification
of novel, evolutionarily conserved Cdc42p-interacting proteins and of redundant
pathways
linking Cdc24p and Cdc42p to actin polarization in
yeast. Molecular Biology of the Cell 11: 773-793
Kim, J.-H., J.-S. Kang, and C.S.M. Chan (1999) Sli15 associates with the Ipl1
protein
kinase to promote proper chromosome segregation
in Saccharomyces cerevisiae. The Journal of Cell Biology 145: 1381-1394
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