Ste20-PAK Signaling in Budding Yeast
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Ste20-PAK Signaling in Budding Yeast
Protein kinases of the PAK (p21-Activated Kinase) family are found in all eukaryotic species. This family is defined by sequence similarity in the kinase domains and by the occurrence of a domain that can be bound by CDC42, a p21 GTPase of the Ras superfamily. Saccharomyces cerevisiae cells contain three members of this family, Ste20, Cla4, and Skm1, each of which performs a distinct set of cellular roles. Like all members of the PAK family, these three kinases contain an N-terminal PBD and a C-terminal protein kinase domain; however, Cla4 and Skm1 also contain a PH domain N-terminal to the PBD and, together with PAK2 from Schizosaccharomyces pombe, form a distinct subfamily (Ref.1).

The Ste20 group kinases are further divided into the PAK and GCK (Germinal Center Kinase) families. They are characterized by the presence of a conserved kinase domain and a noncatalytic region of great structural diversity that enables the kinases to interact with various signaling molecules and regulatory proteins of the cytoskeleton. Ste20 signal upstream of several MAPKs (Mitogen-Activated Protein Kinase, Kss1 or Fus3), MAP2K (Ste7) and MAP3K (Ste11) cascades in response to extracellular mating pheromones, filamentous growth, and high osmolarity. The pheromones bind to GPCR (G Protein-Coupled Receptors) Ste2/Ste3 and trigger release of Gpa1, Ste18 and Ste4, which activate Ste20. This brings the Ste5-associated kinase Ste11 into close proximity with Ste20. BMH1/2 (Brain Modulosignalin Homolog-1/2), yeast orthologs of mammalian 14-3-3 adaptor proteins, associates with Ste20 and are required for invasive growth. The methyltransferase Hsl7 negatively regulates Ste20 function by binding to the N-terminal region of Ste20, competing with CDC42 (Ref.2). Boi1 (and its structural homolog Boi2) also associates (directly or indirectly) with GTP-bound CDC42, but its biochemical properties are still unknown.

Activation of CDC42 by its exchange factor CDC24 is required to organize the actin cytoskeleton towards the incipient bud site or towards the pheromone-secreting partner during mating. Until the time of bud emergence, CDC24 resides in the nucleus in a complex with the adaptor protein Far1. Concomitantly with bud emergence, CDC28 phosphorylates Far1, inducing its ubiquitin-dependent degradation and promoting the release of CDC24 from the complex. CDC24 then translocates to the incipient bud site where, together with the adaptor protein Bem1, it activates CDC42. Once activated,CDC42 is able to interact with its effectors (Ref.3). Ras2 is an upstream activator of the invasive growth pathway and acts through CDC24. The CDC24-Bem1 complex binds to the plasma membrane either through an interaction between CDC24 and the GTP-bound Rsr1/Bud1 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 and recycles to the bud site or become available for nucleotide exchange later in the cell cycle. Activated GTP-bound CDC42 interacts with Ste20 and this complex binds to the Bni1 scaffold protein. Bni1 also bind to a number of other proteins that interact with the actin cytoskeletal network, including Bud6 and Spa2 (Ref.4). These proteins contribute to anchor the mitotic spindle to the cell cortex because these components localize to the incipient bud site in the G1-phase of the cell cycle and maintain cell polarity.

Ste20, together with the related protein Cla4, is also required for many of the polarity changes that occur during the vegetative growth cycle, including bud emergence (late G1-Phase) and polarized growth of budded cells (G2/M-Phase), as well as for cell division. During bud emergence, Ste20 is phosphorylated by the CDK-cyclin complex CDC28-Cln1/2, and acts upon Myo3/5 and Bni1 to regulate the actin cytoskeleton during polarized growth. The switch from apical to isotropic bud growth (G2/M-Phase) is regulated by CDC28-Clb2. In addition to its role in the pheromone response pathway, Ste20p is necessary for the Cdc42p-dependent induction of filamentous growth (Ref.5).