Editing Cell growth (section)

=== Yeast cell size regulation ===
The relationship between cell size and [[cell division]] has been extensively studied in [[yeast]]. For some cells, there is a mechanism by which cell division is not initiated until a cell has reached a certain size. If the nutrient supply is restricted (after time t = 2 in the diagram, below), and the rate of increase in cell size is slowed, the time period between cell divisions is increased.<ref>{{cite journal |author1=Slavov N. |author2=Botstein D. |title=Coupling among Growth Rate Response, Metabolic Cycle and Cell Division Cycle in Yeast |journal=Molecular Biology of the Cell |volume=22 |pages=1997–2009|date=June 2011 |pmid=21525243 |doi=10.1091/mbc.E11-02-0132 |issue=12 |pmc=3113766}}</ref> Yeast cell-size mutants were isolated that begin cell division before reaching a normal/regular size (''wee'' mutants).<ref>''Wee1'' mutants of ''[[Schizosaccharomyces pombe|S. pombe]]'' have [https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=books&doptcmdl=GenBookHL&term=Wee1+AND+mcb%5Bbook%5D+AND+106201%5Buid%5D&rid=mcb.section.3496#3501 small cell size] and the homologous proteins in humans also [https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=books&doptcmdl=GenBookHL&term=Wee1+AND+mcb%5Bbook%5D+AND+106241%5Buid%5D&rid=mcb.section.3553#3562 regulate cell entry into mitosis]; in {{cite book
| veditors = Lodish HF, Berk A, Zipursky LS, Matsudaira P
| title = Molecular cell biology
| edition = 4th
| publisher = W.H. Freeman
| location = New York
| year = 2000
| isbn = 978-0-7167-3136-8
| display-editors = etal
| url-access = registration
| url = https://archive.org/details/molecularcellbio00lodi
}}</ref>
[[File:Cellcycle and growth.png|thumbnail|Figure 1:Cell cycle and growth]]

[[Wee1]] protein is a [[tyrosine kinase]] that normally phosphorylates the Cdc2 cell cycle regulatory protein (the homolog of [[CDK1]] in humans), a cyclin-dependent kinase, on a tyrosine residue. Cdc2 drives entry into mitosis by phosphorylating a wide range of targets. This [[covalent]] modification of the molecular structure of Cdc2 inhibits the enzymatic activity of Cdc2 and prevents cell division. Wee1 acts to keep Cdc2 inactive during early [[G2 phase|G2]] when cells are still small. When cells have reached sufficient size during G2, the phosphatase [[Cdc25]] removes the inhibitory phosphorylation, and thus activates Cdc2 to allow mitotic entry. A balance of Wee1 and Cdc25 activity with changes in cell size is coordinated by the mitotic entry control system. It has been shown in Wee1 mutants, cells with weakened Wee1 activity, that Cdc2 becomes active when the cell is smaller. Thus, mitosis occurs before the yeast reach their normal size. This suggests that cell division may be regulated in part by dilution of Wee1 protein in cells as they grow larger.

====Linking Cdr2 to Wee1====
The protein kinase [[CDR2 (gene)|Cdr2]] (which negatively regulates Wee1) and the Cdr2-related kinase [[CDR1 (gene)|Cdr1]] (which directly phosphorylates and inhibits Wee1 ''in vitro'')<ref>{{cite journal |vauthors=Wu L, Russell P |title=Nim1 kinase promotes mitosis by inactivating Wee1 tyrosine kinase |journal=Nature |volume=363 |issue=6431 |pages=738–41 |date=June 1993 |pmid=8515818 |doi=10.1038/363738a0|bibcode = 1993Natur.363..738W |s2cid=4320080 }}</ref> are localized to a band of cortical nodes in the middle of interphase cells. After entry into mitosis, cytokinesis factors such as [[myosin II]] are recruited to similar nodes; these nodes eventually condense to form the [[cytokinesis|cytokinetic]] ring.<ref>{{cite journal |doi=10.1016/S1534-5807(03)00324-1 |vauthors=Wu JQ, Kuhn JR, Kovar DR, Pollard TD |title=Spatial and temporal pathway for assembly and constriction of the contractile ring in fission yeast cytokinesis |journal=Dev. Cell |volume=5 |issue=5 |pages=723–34 |date=November 2003 |pmid=14602073 |doi-access=free }}</ref> A previously uncharacterized protein, [[leukotriene B4 receptor|Blt1]], was found to colocalize with Cdr2 in the medial interphase nodes. Blt1 knockout cells had increased length at division, which is consistent with a delay in mitotic entry. This finding connects a physical location, a band of cortical nodes, with factors that have been shown to directly regulate mitotic entry, namely Cdr1, Cdr2, and Blt1.

Further experimentation with [[green fluorescent protein|GFP]]-tagged proteins and mutant proteins indicates that the medial cortical nodes are formed by the ordered, Cdr2-dependent assembly of multiple interacting proteins during interphase. Cdr2 is at the top of this hierarchy and works upstream of Cdr1 and Blt1.<ref name=Moseley09>{{cite journal |vauthors=Moseley JB, Mayeux A, Paoletti A, Nurse P |title=A spatial gradient coordinates cell size and mitotic entry in fission yeast |journal=Nature |volume=459 |issue=7248 |pages=857–60 |date=June 2009 |pmid=19474789 |doi=10.1038/nature08074 |bibcode=2009Natur.459..857M|s2cid=4330336 }}</ref> Mitosis is promoted by the negative regulation of Wee1 by Cdr2. It has also been shown that Cdr2 recruits Wee1 to the medial cortical node. The mechanism of this recruitment has yet to be discovered. A Cdr2 kinase mutant, which is able to localize properly despite a loss of function in phosphorylation, disrupts the recruitment of Wee1 to the medial cortex and delays entry into mitosis. Thus, Wee1 localizes with its inhibitory network, which demonstrates that mitosis is controlled through Cdr2-dependent negative regulation of Wee1 at the medial cortical nodes.<ref name=Moseley09/>

==== Cell polarity factors ====
Cell polarity factors positioned at the cell tips provide spatial cues to limit Cdr2 distribution to the cell middle. In fission yeast ''[[Schizosaccharomyces pombe]]'' (''S. Pombe''), cells divide at a defined, reproducible size during mitosis because of the regulated activity of Cdk1.<ref>{{cite journal |doi=10.1016/S0168-9525(02)02745-2 |author=Rupes I |title=Checking cell size in yeast |journal=Trends Genet. |volume=18 |issue=9 |pages=479–85 |date=September 2002 |pmid=12175809 }}</ref> The cell polarity protein kinase [[Pom1]], a member of the dual-specificity tyrosine-phosphorylation regulated kinase (DYRK) family of kinases, localizes to cell ends. In Pom1 knockout cells, Cdr2 was no longer restricted to the cell middle, but was seen diffusely through half of the cell. From this data it becomes apparent that Pom1 provides inhibitory signals that confine Cdr2 to the middle of the cell. It has been further shown that Pom1-dependent signals lead to the phosphorylation of Cdr2. Pom1 knockout cells were also shown to divide at a smaller size than wild-type, which indicates a premature entry into mitosis.<ref name=Moseley09/>

Pom1 forms polar gradients that peak at cell ends, which shows a direct link between size control factors and a specific physical location in the cell.<ref>{{cite journal |vauthors=Padte NN, Martin SG, Howard M, Chang F |title=The cell-end factor pom1p inhibits mid1p in specification of the cell division plane in fission yeast |journal=Curr. Biol. |volume=16 |issue=24 |pages=2480–7 |date=December 2006 |pmid=17140794 |doi=10.1016/j.cub.2006.11.024 |doi-access=free |bibcode=2006CBio...16.2480P }}</ref> As a cell grows in size, a gradient in Pom1 grows. When cells are small, Pom1 is spread diffusely throughout the cell body. As the cell increases in size, Pom1 concentration decreases in the middle and becomes concentrated at cell ends. Small cells in early G2 which contain sufficient levels of Pom1 in the entirety of the cell have inactive Cdr2 and cannot enter mitosis. It is not until the cells grow into late G2, when Pom1 is confined to the cell ends that Cdr2 in the medial cortical nodes is activated and able to start the inhibition of Wee1. This finding shows how cell size plays a direct role in regulating the start of mitosis. In this model, Pom1 acts as a molecular link between cell growth and mitotic entry through a Cdr2-Cdr1-Wee1-Cdk1 pathway.<ref name=Moseley09/> The Pom1 polar gradient successfully relays information about cell size and geometry to the Cdk1 regulatory system. Through this gradient, the cell ensures it has reached a defined, sufficient size to enter mitosis.