CDC42-Rho Interactions in S. cerevisiae
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CDC42-Rho Interactions in S. cerevisiae

Cell Polarity is an essential characteristic of virtually every cell type. The budding yeast S. cerevisiae (Saccharomyces cerevisiae) has been critical for elucidation of proteins and mechanisms that underlie Cell Polarity development. Polarized Growth is mediated by a series of steps involving cortical landmarks, Rho GTPases and a polarized Actin cytoskeleton. Actin cortical patches are essential for normal Endocytosis and secretion is targeted to the bud or mating projection, allowing selective growth in that area. Patches are associated with invaginations of the plasma membrane and occur in polarized clusters at regions of cell growth in budding cells. One of the crucial Rho type GTPases is CDC42 (Cell Division Control Protein-42) which facilitates decisive event for the establishment and maintenance of Cell polarity. CDC42 is prenylated with a C20 Geranylgeranyl isoprene group at a C-terminal Cys residue and is necessary for the membrane attachment of CDC42 (Ref.1). The CDC24 (Cell Division Control Protein-24)-Bem1 (Bem1 Protein) Complex binds to the plasma membrane either through an interaction between CDC24 and the GTP-bound Rsr1 (Ras-Related Protein-Rsr1) GTPase, which is already at the plasma membrane at the site of incipient Bud Emergence, or through the CDC24 PH domain. CDC24 catalyzes the dissociation of GDP from CDC42 and GDP is replaced by GTP. As a result of this biochemical exchange reaction, CDC24 dissociates from both CDC42 and Bem1, which then interact with Rsr1, which is GDP bound through the action of the Bud2 (Inhibitory Regulator Protein-Bud2/Cla2) GAP and Bud5 (Bud Site Selection Protein-Bud5) (Ref.2).

Exogenous Mating-Factor Pheromone activates GTP-bound CDC42, which then interacts with GIC1 (GTPase-Interacting Component-1) and/or GIC2 (GTPase-Interacting Component-2) and/or one of the family of PAK-Like Kinases (Cla4 (Serine/Threonine-Protein Kinase-Cla4) and Ste20), and this complex binds to the Bni1 scaffold protein. The Bem1, via its two SH3 domains, interacts with Boi1 (Bem1-Binding Protein) and Boi2. Boi1 and Boi2 acts as regulators of bud initiation and the secretory apparatus (Ref.3). The action of one or more CDC42-GAPs (Bem3, RGA1 (Rho-Type GTPase-Activating Protein-1) and RGA2) is necessary for the conversion of CDC42-GTP to a GDP-bound state. Bni1 along with Pfy1 (Profilin), MSB3 (Multicopy Suppressor of Bud Emergence-3), and Spa2 enhances the function of Actin cytoskeletal network during bud emergence. Among the PAK-Like Kinases, activated Cla4 mediates Actin nucleation and assembly through activation of Sla2 (Sla2 Protein) and ABP1 (Actin Binding Protein); whereas Ste20 mediated Bud8 activation is necessary for Actin assembly and Cytokinesis. An interaction between GIC1, GIC2, CAP1 (F-Actin Capping Protein-Alpha Subunit), Bub2  and Ste50 plays an essential role in regulating Apical Growth whereas GIC1-2/Hof1 interaction results in Cytokinesis; and therefore, a potential novel link between CDC42 and the Actin cytoskeleton (Ref.4 & 5).

The RhoGTPase is another major regulator of cell polarity and cell wall synthesis in S. cerevisiae. The GTP-bound form of Rho activates 1,3-Beta-Glucan Synthase, which catalyzes the synthesis of the major structural component of the cell wall and activates PKC1 (Protein Kinase-C Like-1), which controls cell wall metabolism and Actin polarity. PKC1 acts as an effector for both CDC24 and Rho (Ref.6). This interaction is quite interesting and a potential means for PKC1 to regulate CDC42 function. Cell wall stress induces hyperactivation of Rho, which in turn results in a transient loss of Actin polarity in order to depolarize cell wall synthesis and repair widespread cell wall damage. Rho interacts with RGA1 resulting in the conversion of Rho-GTP to a GDP-bound state. Rho interacts with Bem4, Bni1, Boi1, and Boi2 and directs Actin polarity and nuclear migration, in part via an interaction with Pfy1. Zds1 (Zds1 Protein) and Zds2 monitor and regulate CDC42 in response to Rho activation through Cell Wall Stress. Zds proteins interact with Rho, Rho effector Bni1 and Bem4 in order to facilitate Actin Assembly and Cytokinesis during bud emergence. Rho interacts with Shc1 and CHS3 (Chitin Synthase-3), and these proteins are required for maintenance of cell wall integrity under Osmotic Stress. Shc1 expression is up-regulated during Sporulation and it is involved in the CHS3-dependent formation of the spore wall Chitosan layer. Rho also interacts with PFS1 (Prospore Formation at Selected Spindle Poles Protein-1) and Spr6; protein that are required for Sporulation. PFS1 along with Spr6 mediates binding interactions with Actin filaments through Zds activation. Rho further stimulates GIC1-2/Hof1 mediated Cytokinesis through activation of NIP100 (NIP100 Protein), Nfi1 and Septins (CDC11 (Cell Division Control Protein-11) and CDC12). NIP100 is the yeast Dynactin component involved in nuclear division and migration. Bem4 acts synergistically with Rho for activating Septins involved in Vegetative Growth as well as Cytokinesis (Ref.7 & 8).

Polarized growth and budding require the delivery of proteins and lipids to specific sites on the plasma membrane. Under cell cycle control, Exocytosis first becomes localized to regions of cell growth at the presumptive bud site. As a bud emerges, Exocytosis initially localizes to a small region at the bud tip, and then becomes delocalized in the bud and finally it becomes localized to the bud neck, mirroring cortical Actin cytoskeleton organization at each stage. The Rho-CDC42 interaction with elements of the Exocytic machinery controls transport of Secretory vesicles and vesicle docking and fusion at the plasma membrane. Vesicle fusion occurs through an interaction with Exo70 (70 kDa Exocyst Complex Protein), a component of the Exocyst Complex. The vesicle-docking protein Sro77 (Sro77 Protein) is implicated in Regulatory, Cytoskeletal and Endocytic roles (Ref.2). Sro77 interacts with Apg17, NIP100 and Ent2 (a Clathrin-binding protein) during the internalization step of Endocytosis. Sro77 also coordinate Exocytosis. Ent2 gets activated by CDC24 during Endocytosis. In budding cells, activation of the Rsr1 GTPase, recruits and activates CDC42 via interaction with CDC24. CDC42 interacts with several proteins that are presumed to be effectors that transduce its signal to bring about polarization of the Actin cytoskeleton. Actin cables serve as tracks for vesicle, organelle and mRNA transport, whereas cortical Actin patches are important for Endocytosis. Rho activates Apg17, a protein that regulates Autophagy. Apg17 further interacts with several proteins, including NIP100, Sro77 and Exocyst Complex. Hence Apg17 has a vital role in Cytokinesis and Autophagy. Interactions between Apg17 and NIP100, Sro77 and Exo84 are a part of a mechanism coordinating nuclear migration, Actomyosin ring contraction, and Exocytosis during Cytokinesis or Autophagy (Ref.1).

Thus the establishment of Cell Polarity and Polarized Growth is crucial for the development. On a cellular level, polarity results in the generation and maintenance of shape, directional movement, Phagocytosis, Adhesion and Motility. All these changes require dynamic assembly and rearrangements of the Actin cytoskeleton, which are orchestrated by local activation and of Rho-type GTPases (Ref.1). Connections between Rho- and CDC42-pathways, regulate Polarity establishment, Actin assembly and the morphogenesis checkpoint. This network of interactions provides an integrated response of signaling proteins, the cytoskeleton, and organelles to the cues that direct Polarity development (Ref.9).