Protein kinase Cdc15 activates the Dbf2-Mob1 kinase complex

Mah, Angie S.; Jang, Joanne; Deshaies, Raymond J.

doi:10.1073/pnas.141098998

Cited by 186 publications

(208 citation statements)

References 42 publications

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“…Based on homology to the RAM, MEN, and SIN pathways (Mah et al, 2001;Hou et al, 2003;Nelson et al, 2003), it seemed likely that one or more of the Drosophila mob genes would function along with trc and fry. We found evidence supporting this hypothesis but the results were complicated by both pleiotropy and redundancy.…”

Section: Trc Dmob and Fry Function In A Common Signaling Pathwaymentioning

confidence: 99%

“…The Ndr kinases are members of a subfamily of serine/threonine kinases that includes Sax1 (Caenorhabditis elegans), Cbk1 (Saccharomyces cerevisiae), Dbf2 (S. cerevisiae), Warts/Lats (Drosophila), Orb6 (Schizosaccharomyces pombe) and Cot-1 (Neurospora), which regulate cell growth, cell division and cell morphology (Yarden et al, 1992;Justice et al, 1995;Xu et al, 1995;Verde et al, 1998;Zallen et al, 2000). In S. cerevisiae Cbk1 and Dbf2/Dbf20 play central roles in the RAM (regulation of AceII activity and cellular morphogenesis) and MEN (mitotic exit network) pathways (Mah et al, 2001;Nelson et al, 2003). Mutants of Cbk1 or other RAM pathway genes including its binding partners Mob2 and Tao3 (Pag1) fail to activate the AceII transcription factor in daughter cells and result in rounder than normal cells due to a defect in axial growth of the bud (Colman-Lerner et al, 2001;Du and Novick, 2002;Nelson et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…A similar situation exists for the related Dbf2 kinase, which is a component of the mitotic exit network (MEN). Dbf2 binds to Mob1 (which is related to Mob2) and this complex is essential for activity (Mah et al, 2001). Similarly, S. pombe Mob2 interacts physically with the Orb6 protein kinase and is required for Orb6 function in the coordination of cell polarity with the cell cycle (Hou et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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DrosophilaMob Family Proteins Interact with the Related Tricornered (Trc) and Warts (Wts) Kinases

Emoto

Fang

et al. 2005

MBoC

127

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The function of Tricornered (Trc), the Drosophila Ndr (Nuclear Dbf2-related) serine/threonine protein kinase, is required for the normal morphogenesis of a variety of polarized outgrowths including epidermal hairs, bristles, arista laterals, and dendrites. In yeast the Trc homolog Cbk1 needs to bind Mob2 to activate the RAM pathway. In this report, we provide genetic and biochemical data that Drosophila Trc also interacts with and is activated by Drosophila Dmob proteins. In addition, Drosophila Mob proteins appear to interact with the related Warts/Lats kinase, which functions as a tumor suppressor in flies and mammals. Interestingly, the overgrowth tumor phenotype that results from mutations in Dmob1 (mats) was only seen in genetic mosaics and not when the entire animal was mutant. We conclude that unlike in yeast, in Drosophila individual Mob proteins interact with multiple kinases and that individual NDR family kinases interact with multiple Mob proteins. We further provide evidence that Mo25, the Drosophila homolog of the RAM pathway hym1 gene does not function along with Trc.

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Section: Trc Dmob and Fry Function In A Common Signaling Pathwaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

DrosophilaMob Family Proteins Interact with the Related Tricornered (Trc) and Warts (Wts) Kinases

Emoto

Fang

et al. 2005

MBoC

127

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“…It phosphorylates one of the GAP components, Bfa1, and frees Tem1 from the inhibition by Bfa1 (Hu et al, 2001;Lee et al, 2001b). Tem1-GTP is believed to activate a downstream protein kinase Cdc15, which then activates the protein kinase Dbf2 in a manner dependent on the Dbf2 associated factor Mob1 (Komarnitsky et al, 1998;Mah et al, 2001). We have identified a new mechanism that inactivates MEN through the induction of Amn1 protein upon MEN activation.…”

Section: Introductionmentioning

confidence: 99%

Phosphatase 2A Negatively Regulates Mitotic Exit inSaccharomyces cerevisiae

Wang

2006

MBoC

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In budding yeast Saccharomyces cerevisiae, Cdc5 kinase is a component of mitotic exit network (MEN), which inactivates cyclin-dependent kinase (CDK) after chromosome segregation. cdc5-1 mutants arrest at telophase at the nonpermissive temperature due to the failure of CDK inactivation. To identify more negative regulators of MEN, we carried out a genetic screen for genes that are toxic to cdc5-1 mutants when overexpressed. Genes that encode the B-regulatory subunit (Cdc55) and the three catalytic subunits (Pph21, Pph22, and Pph3) of phosphatase 2A (PP2A) were isolated. In addition to cdc5-1, overexpression of CDC55, PPH21, or PPH22 is also toxic to other temperature-sensitive mutants that display defects in mitotic exit. Consistently, deletion of CDC55 partially suppresses the temperature sensitivity of these mutants. Moreover, in the presence of spindle damage, PP2A mutants display nuclear localized Cdc14, the key player in MEN pathway, indicative of MEN activation. All the evidence suggests the negative role of PP2A in mitotic exit. Finally, our genetic and biochemical data suggest that PP2A regulates the phosphorylation of Tem1, which acts at the very top of MEN pathway. INTRODUCTIONThe key driving force for cell division in all eukaryotic cells is the conserved cyclin-dependent kinase (CDK). CDK activity fluctuates during the cell cycle, peaking at the S and M phases and dropping at the G1 phase. Although the high CDK activity is required for DNA duplication and chromosome segregation, the low CDK activity at late M and G1 phase is essential for the loading of DNA replication complexes onto replication origins (Noton and Diffley, 2000;Lengronne and Schwob, 2002). Thus, cells have developed a signal transduction pathway, named the mitotic exit network (MEN), to inactivate CDK after mitosis (Morgan, 1999). The components of the MEN pathway include protein kinases Cdc5, Cdc15, Dbf2, a GTPase Tem1, a phosphatase Cdc14, and a Dbf2 binding protein Mob1 Luca and Winey, 1998;Lee et al., 2001a). Phosphatase Cdc14, the key player in the MEN pathway, dephosphorylates Cdh1, an activator for APC (anaphase promoting complex), and subsequently activates the degradation of a Btype cyclin, Clb2. Cdc14 also enhances the stability of Sic1 protein, which acts as a CDK inhibitor (Visintin et al., 1998). During most of the cell cycle, Cdc14 is localized in the nucleolus, but its translocation out of the nucleolus in anaphase and telophase allows it to encounter its substrates, such as Cdh1 and Sic1. All the components in the MEN pathway are required for the release of Cdc14 from the nucleolus, suggesting that Cdc14 acts downstream of MEN pathway (Shou et al., 1999;Visintin et al., 1999).The regulation of MEN activity is achieved through the multilayer control of Tem1, a small GTPase that localizes at the spindle pole body (SPB) and acts on the very top of the MEN pathway. Tem1's activator, the GTPase exchange factor (GEF) Lte1, exhibits daughter-cell specific localization. Thus, SPB-localized Tem1 is activated after it encounters...

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“…Tem1 activity is thought to be regulated both by the putative GTP exchange factor (GEF) Lte1 and a two-component GTPase-activating protein (GAP) complex composed of Bub2 and Bfa1 (reviewed in Bardin and Amon, 2001;McCollum and Gould, 2001). Tem1-GTP is believed to activate the protein kinase Cdc15, which then activates the protein kinase Dbf2 in a manner dependent on the Dbf2-associated factor Mob1 (Lee et al, 2001;Mah et al, 2001;Visintin and Amon, 2001). The spindle pole body (SPB) component Nud1 functions as a scaffold for MEN components at the SPB (Gruneberg et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

The Role of the Polo Kinase Cdc5 in Controlling Cdc14 Localization

Visintin

Stegmeier

Amon

2003

MBoC

119

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In budding yeast, the protein phosphatase Cdc14 controls exit from mitosis. Its activity is regulated by a competitive inhibitor Cfi1/Net1, which binds to and sequesters Cdc14 in the nucleolus. During anaphase, Cdc14 is released from its inhibitor by the action of two regulatory networks. The Cdc Fourteen Early Anaphase Release (FEAR) network initiates Cdc14 release from Cfi1/Net1 during early anaphase, and the Mitotic Exit Network (MEN) promotes Cdc14 release during late anaphase. Here, we investigate the relationship among FEAR network components and propose an order in which they function to promote Cdc14 release from the nucleolus. Furthermore, we examine the role of the protein kinase Cdc5, which is a component of both the FEAR network and the MEN, in Cdc14 release from the nucleolus. We find that overexpression of CDC5 led to Cdc14 release from the nucleolus in S phase-arrested cells, which correlated with the appearance of phosphorylated forms of Cdc14 and Cfi1/Net1. Cdc5 promotes Cdc14 phosphorylation and, by stimulating the MEN, Cfi1/Net1 phosphorylation. Furthermore, we suggest that Cdc14 release from the nucleolus only occurs when Cdc14 and Cfi1/Net1 are both phosphorylated.

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Protein kinase Cdc15 activates the Dbf2-Mob1 kinase complex

Cited by 186 publications

References 42 publications

DrosophilaMob Family Proteins Interact with the Related Tricornered (Trc) and Warts (Wts) Kinases

DrosophilaMob Family Proteins Interact with the Related Tricornered (Trc) and Warts (Wts) Kinases

Phosphatase 2A Negatively Regulates Mitotic Exit inSaccharomyces cerevisiae

The Role of the Polo Kinase Cdc5 in Controlling Cdc14 Localization

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