Control of Lte1 Localization by Cell Polarity Determinants and Cdc14

Seshan, Anupama; Bardin, Allison J.; Amon, Angelika

doi:10.1016/s0960-9822(02)01388-x

Cited by 76 publications

(131 citation statements)

References 40 publications

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“…This phenotype is thought to occur in part because septin assembly at the incipient bud site is defective (28), which activates a morphogenesis checkpoint that inhibits cyclin-cdk (Clb-Cdc28) complexes required to drive G 2 /M progression (57). A second phenotype of cla4⌬ cells is a delay in mitotic exit (11)(12)(13). Mitotic exit is impaired because recent studies have indicated that Cla4 is required for phosphorylation of Lte1 (11,12), a guanine-nucleotide exchange factor for the Tem1 GTPase in the MEN (58).…”

Section: Resultsmentioning

confidence: 99%

“…A second phenotype of cla4⌬ cells is a delay in mitotic exit (11)(12)(13). Mitotic exit is impaired because recent studies have indicated that Cla4 is required for phosphorylation of Lte1 (11,12), a guanine-nucleotide exchange factor for the Tem1 GTPase in the MEN (58). Cla4 is also required for Lte1 function as assessed by restricted localization of this exchange factor to the cortex of the bud (11).…”

Section: Resultsmentioning

confidence: 99%

“…Cla4 is also required for Lte1 function as assessed by restricted localization of this exchange factor to the cortex of the bud (11). Indeed, in cla4⌬ cells Lte1 localizes to the cortex of mother and bud, resulting in a delay in mitotic exit (11,12).…”

Section: Resultsmentioning

confidence: 99%

“…from mitosis (mitotic exit network (MEN)) 1 (11)(12)(13), and stimulates docking and fusion of the lysosome-like vacuole (14 -16). Phosphoinositide signaling has several functions in yeast.…”

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confidence: 99%

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The p21-activated Protein Kinase-related Kinase Cla4 Is a Coincidence Detector of Signaling by Cdc42 and Phosphatidylinositol 4-Phosphate

Wild

Lemmon

et al. 2004

Journal of Biological Chemistry

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Signal transduction pathways that co-regulate a given biological process often are organized into networks by molecules that act as coincidence detectors. Phosphoinositides and the Rho-type GTPase Cdc42 regulate overlapping processes in all eukaryotic cells. However, the coincidence detectors that link these pathways into networks remain unknown. Here we show that the p21-activated protein kinase-related kinase Cla4 of yeast integrates signaling by Cdc42 and phosphatidylinositol 4-phosphate (PI4P). We found that the Cla4 pleckstrin homology (PH) domain binds in vitro to several phosphoinositide species. To determine which phosphoinositides regulate Cla4 in vivo, we analyzed phosphatidylinositol kinase mutants (stt4, mss4, and pik1). This indicated that the plasma membrane pool of PI4P, but not phosphatidylinositol 4,5-bisphosphate or the Golgi pool of PI4P, is required for localization of Cla4 to sites of polarized growth. A combination of the Cdc42-binding and PH domains of Cla4 was necessary and sufficient for localization to sites of polarized growth. Point mutations affecting either domain impaired the ability of Cla4 to regulate cell morphogenesis and the mitotic exit network (localization of Lte1). Therefore, Cla4 must retain the ability to bind both Cdc42 and phosphoinositides, the hallmark of a coincidence detector. PI4P may recruit Cla4 to the plasma membrane where Cdc42 activates its kinase activity and refines its localization to cortical sites of polarized growth. In mammalian cells, the myotonic dystrophy-related Cdc42-binding kinase possesses p21-binding and PH domains, suggesting that this kinase may be a coincidence detector of signaling by Cdc42 and phosphoinositides.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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The p21-activated Protein Kinase-related Kinase Cla4 Is a Coincidence Detector of Signaling by Cdc42 and Phosphatidylinositol 4-Phosphate

Wild

Lemmon

et al. 2004

Journal of Biological Chemistry

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“…Probably the best characterized function of Cla4 is the assembly of the septin ring, which plays a fundamental role in cytokinesis and cell compartmentalization (Weiss et al, 2000;Schmidt et al, 2003;Kadota et al, 2004;Versele and Thorner, 2004). In addition, Cla4 regulates mitotic entry and exit (Hö fken and Schiebel, 2002;Seshan et al, 2002;Sakchaisri et al, 2004). Very little is known about Skm1, and no clear function has been attributed to this PAK (Martín et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

The Cdc42 Effectors Ste20, Cla4, and Skm1 Down-Regulate the Expression of Genes Involved in Sterol Uptake by a Mitogen-activated Protein Kinase-independent Pathway

Lin

Unden

Jacquier

et al. 2009

MBoC

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In Saccharomyces cerevisiae, the Rho-type GTPase Cdc42 regulates polarized growth through its effectors, including the p21-activated kinases (PAKs) Ste20, Cla4, and Skm1. Previously, we demonstrated that Ste20 interacts with several proteins involved in sterol synthesis that are crucial for cell polarization. Under anaerobic conditions, sterols cannot be synthesized and need to be imported into cells. Here, we show that Ste20, Cla4, and Skm1 form a complex with Sut1, a transcriptional regulator that promotes sterol uptake. All three PAKs can translocate into the nucleus and down-regulate the expression of genes involved in sterol uptake, including the Sut1 targets AUS1 and DAN1 by a novel mechanism. Consistently, deletion of either STE20, CLA4, or SKM1 results in an increased sterol influx and PAK overexpression inhibits sterol uptake. For Ste20, we demonstrate that the down-regulation of gene expression requires nuclear localization and kinase activity of Ste20. Furthermore, the Ste20-mediated control of expression of sterol uptake genes depends on SUT1 but is independent of a mitogen-activated protein kinase signaling cascade. Together, these observations suggest that PAKs translocate into the nucleus, where they modulate expression of sterol uptake genes via Sut1, thereby controlling sterol homeostasis. INTRODUCTIONThe small Rho GTPase Cdc42 plays a central role in the regulation of cellular polarity in eukaryotic cells (EtienneManneville, 2004;Jaffe and Hall, 2005). In the budding yeast Saccharomyces cerevisiae, Cdc42 regulates different types of polarized growth during various phases of its life cycle, including budding during vegetative growth, mating between haploid cells of opposite mating types, and filamentous growth upon nutrient limitation (Park and Bi, 2007). Cdc42 promotes polarized growth through multiple pathways, including polarization of the actin cytoskeleton and directed vesicle trafficking. Among the Cdc42 effectors that trigger these pathways are Ste20, Cla4 and Skm1, members of the p21-activated kinase (PAK) family of serine/threonine protein kinases (Hofmann et al., 2004;Park and Bi, 2007).Cdc42 recruits Ste20 and Cla4 from the cytoplasm and activates them at the plasma membrane at sites of polarized growth. Therefore, Ste20 and Cla4 are enriched at tips of buds and mating projections (Peter et al., 1996;Leberer et al., 1997;Holly and Blumer, 1999). The recruitment of Ste20 and Cla4 to these sites is governed by protein-protein as well as protein-lipid interactions. PAKs carry a conserved Cdc42/ Rac-interactive binding (CRIB) domain that mediates binding to Cdc42 and regulates their activity (Cvrckova et al., 1995;Peter et al., 1996;Leberer et al., 1997;Lamson et al., 2002;Ash et al., 2003). Ste20 and Cla4 also bind to Bem1, a scaffold protein that brings Cdc42, its activator Cdc24 and either Ste20 or Cla4, into proximity (Leeuw et al., 1998;Gulli et al., 2000;Bose et al., 2001;Yamaguchi et al., 2007). In addition, phosphoinositide-binding domains promote the association with membrane lip...

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