CDC42-Actin Interactions in S. cerevisiae
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CDC42-Actin Interactions in S. cerevisiae

Actin cortical patches are one of the major cytoskeletal structures in yeast and are essential for normal Endocytosis, Cell Growth and Morphology. Actin cortical patches are associated with invaginations of the plasma membrane and occur in polarized clusters at regions of cell growth in budding cells (Ref.1). Patch Assembly probably begins with the association of assembly factors recruited to the plasma membrane by CDC42 (Cell Division Control Protein-42) and its associated proteins and is then followed by nucleation of Actin filaments and Actin-dependent association of proteins regulating filament assembly and stability. Prior to bud emergence in S. cerevisiae (Saccharomyces cerevisiae), cells polarize the Actin cytoskeleton toward the future bud site and assemble a Septin ring at that site. Reorganization of both Actin and Septins requires the small GTPase CDC42 and its exchange factor CDC24 (Cell Division Control Protein-24) (Ref.2).

In S. cerevisiae CDC42 is associated with a C20 Geranylgeranyl Isoprene group at a C-terminal Cys residue, and this prenylation is necessary for the membrane attachment of CDC42. This localization of CDC42 at different sites of Polarized Growth during the S. cerevisiae cell cycle is mirrored by the localization of the Actin cytoskeletal network (Ref.3). The CDC24-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 catalyze 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/Cla2 GAP and Bud5. Released CDC24 is free to recycle to the bud site or become available for nucleotide exchange later in the cell cycle. 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. The action of one or more CDC42-GAPs (Bem3 (GTPase-Activating Protein-Bem3), RGA1 (Rho-Type GTPase-Activating Protein-1) and RGA2 (Rho-Type GTPase-Activating Protein-2)) is necessary for the conversion of CDC42-GTP to a GDP-bound state (Ref.3 & 4). CDC42 interacts with GIC2 (GTPase-Interacting Component-2) and/or one of the family of PAK-Like Kinases (Cla4 (Serine/Threonine-Protein Kinase-Cla4), Ste20 and Skm1 (Serine/Threonine-Protein Kinase-Skm1)). These proteins, along with other Actin-binding proteins like Bee1, Sla1 (Cytoskeleton Assembly Control Protein-Sla1), Sla2 (Sla2 Protein) nucleates the localized assembly of the Septins, Chitins and Myo1 (Myosin-1) rings and the subsequent polymerization of Actin at the bud tip, leading to Bud emergence and Apical Bud Growth. Activated GTP-bound CDC42 also interacts with Cla4 as well as with Iqg1 (Ras GTPase-Activating-Like Protein-Iqg1)/Cyk1 (Cytokinesis Protein-1) through its GRD domain (Ref.5 & 6). An interaction between GIC2, Bee1 and the CAP (subunits of the F-Actin filament Capping Protein), plays an essential role in regulating Actin assembly and therefore is a potential novel link between CDC42 and the Actin cytoskeleton. The localization of cortical Actin at the Mother-Bud neck region, following the contraction of the Actomyosin ring and Cytokinesis leads to Septum formation and eventual cell separation. S. cerevisiae alters its morphology in response to both exogenous and endogenous signals, leading to both Bud Emergence and enlargement during the mitotic cell cycle through the Mating/Pheromone Response pathway in response to exogenous Mating-Factor Pheromones, Pseudohyphal formation and Filamentous Growth in response to Starvation conditions. The primary signaling route leading to Pseudohyphal Growth involves the Ras2 GTPase signaling through CDC42 to several components of the Pheromone Response MAPK (Mitogen-Activated Protein Kinase) Cascade, including Ste20 thereby inducing the expression of genes necessary for Filamentous Growth (Ref.7 & 8).

Sla1, Sla2, Bee1, RVS167 (Reduced Viability Upon Starvation Protein-167), and ABP1 (Actin Binding Protein) function in Actin nucleation and assembly upon activation by Cla4. The Actin monomer binding protein Srv2/CAP (Adenylyl Cyclase-Associated Protein) apparently interacts with Sla1, RVS167 and ABP1 along with Bud6 (Bud Site Selection Protein-Bud6), Pfy1 (Profilin), Bni1 and Spa2 to mediate the association of monomeric Actin with the Actin-nucleating complex. An interaction of Bni1 with Spa2 localizes Bni1 to the bud growth sites, where it mediates reorganization of the Actin cytoskeleton and concentration of polarized growth to bud tips during apical growth. The Cla4 and Skm1 play an important role in regulation of Septin filament organization and Cytokinesis. Interactions between Cla4 and the Cortical patch proteins Sla2 and ABP1 have functions in Cortical Patch Assembly and in Endocytosis, a process that is intimately linked to cortical patches. Cla4 regulates the polarity of cortical patches in a CDC42-dependent manner via an interaction with Sla2. The NH2-terminal region of Cla4, maintains cell polarity, contains proline-rich motifs which act as binding sites for the SH3 domain of Sla1, RVS167, and ABP1 (Ref.8). Sla2 localizes to sites of Polarized Growth independently of Actin and mediates an early step in the polarization of Actin cortical patches. RVS167 also affects Patch Polarization, via the interaction with Sla2. Co-localization of Sla2 with Actin is maximum in un-budded and small-budded cells, implying that its Patch Assembly activity is most important early in the cell cycle. Sla2 interacts with Actin-bundling protein Crn1 (Coronin-Like Protein) and is involved in regulation of the Morphogenesis Checkpoint, along with Swe1 and Hsl7 (Protein Arginine N-methyltransferase-Hsl7). In addition to monitoring the Actin cytoskeleton, Swe1 monitors Septin organization via an interaction with Hsl7 at the bud neck. Despite years of analysis of cell polarity development in budding yeast, Genetic studies may have missed information, due to factors including redundancy, lack of appropriate alleles, homeostasis mechanisms and checkpoints. In total, the large number of interactions that are identified among proteins involved in diverse aspects of Cell Polarity development suggests a high level of integration in the functioning of these proteins (Ref. 1 & 2).