Abstract
Nuclear DBF2p-related (NDR) kinases constitute a functionally conserved protein family of eukaryotic regulators that control cell division and polarity. In fungi, they function as effector kinases of the morphogenesis (MOR) and septation initiation (SIN) networks and are activated by pathway-specific germinal centre (GC) kinases. We characterized a third GC kinase, MST-1, that connects both kinase cascades. Genetic and biochemical interactions with SIN components and life cell imaging identify MST-1 as SIN-associated kinase that functions in parallel with the GC kinase SID-1 to activate the SIN-effector kinase DBF-2. SID-1 and MST-1 are both regulated by the upstream SIN kinase CDC-7, yet in an opposite manner. Aberrant cortical actomyosin rings are formed in Δmst-1, which resulted in mis-positioned septa and irregular spirals, indicating that MST-1-dependent regulation of the SIN is required for proper formation and constriction of the septal actomyosin ring. However, MST-1 also interacts with several components of the MOR network and modulates MOR activity at multiple levels. MST-1 functions as promiscuous enzyme and also activates the MOR effector kinase COT-1 through hydrophobic motif phosphorylation. In addition, MST-1 physically interacts with the MOR kinase POD-6, and dimerization of both proteins inactivates the GC kinase hetero-complex. These data specify an antagonistic relationship between the SIN and MOR during septum formation in the filamentous ascomycete model Neurospora crassa that is, at least in part, coordinated through the GC kinase MST-1. The similarity of the SIN and MOR pathways to the animal Hippo and Ndr pathways, respectively, suggests that intensive cross-communication between distinct NDR kinase modules may also be relevant for the homologous NDR kinases of higher eukaryotes.
Highlights
Coordination of cell growth and division is a fundamental subject in biology
We show that the promiscuous functioning Ste20-related kinase MST-1 has a dual role in regulating septation initiation network (SIN) and MOR network function
SIN and MOR coordination through MST-1 can be achieved in an enzyme-independent manner through hetero-dimerization of germinal centre kinases, providing an additional level for activity regulation of signaling networks that is not dependent on phosphate transfer
Summary
Coordination of cell growth and division is a fundamental subject in biology. Successful cytokinesis relies on the coordinated assembly and activation of an actomyosin-based contractile ring, which must be regulated in a spatially and temporally precise manner [1,2,3]. The underlying molecular pathways are highly complex and involve a large number of components forming elaborate interactive networks Central components of these networks are the highly conserved nuclear Dbf2p-related (NDR) kinases, which are important for morphogenesis and proliferation in all eukaryotes analyzed to date [4,5,6]. The second group of NDR kinases controls polarity as components of a homologous morphogenesis network (the fungal MOR network; homologous to the animal Ndr1/2 pathway) [5] In fungi this pathway plays a critical role in the polar organization of the actin cytoskeleton at cell ends, which seems, at least in part, to be achieved through regulation of Rho-type GTPases [12,13,14,15]. The MOR regulates the expression of multiple genes with cell wall-related functions in unicellular yeasts, including genes required for efficient cell separation [16,17,18]
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