Phosphorylation of Rap1GAP, a striatally enriched protein, by protein kinase A controls Rap1 activity and dendritic spine morphology

McAvoy, Thomas; Zhou, Ming‐Ming; Greengard, Paul; Nairn, Angus C.

doi:10.1073/pnas.0813263106

Cited by 61 publications

(56 citation statements)

References 54 publications

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“…Phosphorylation and dephosphorylation have been shown to regulate GAP function in a number of different eukaryotic cells (Sopko et al 2007;Zheng et al 2007;Toure et al 2008;McAvoy et al 2009;Mori et al 2009;Wolfe et al 2009). Therefore, we hypothesize that PP2A-Pab1 inhibition of Spg1 is more likely to operate indirectly, perhaps through activating dephosphorylation of the Cdc16-Byr4 two-component GAP.…”

Section: Resultsmentioning

confidence: 99%

Antagonistic Roles of PP2A-Pab1 and Etd1 in the Control of Cytokinesis in Fission Yeast

et al. 2010

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In Schizosaccharomyces pombe, Etd1 is a positive regulator of the septation initiation network (SIN), a conserved GTPase-regulated kinase cascade that triggers cytokinesis. Here we show that a mutation in the pab1 gene, which encodes the B-regulatory subunit of the protein phosphatase 2A (PP2A), suppresses mutations in the etd1 gene. Etd1 is required for the function of the GTPase Spg1, a key regulator of SIN signaling. Interestingly, the loss of Pab1 function restored the activity of Spg1 in Etd1-deficient cells. This result suggests that PP2A-Pab1-mediated dephosphorylation inhibits Spg1, thus antagonizing Etd1 function. The loss of pab1 function also rescues the lethality of mutants of other genes in the SIN cascade such as mob1, sid1, and cdc11. Two-hybrid assays indicate that Pab1 physically interacts with Mob1, Sid1, Sid2, and Cdc11, suggesting that the phosphatase 2A B-subunit is a component of the SIN complex. Together, our results indicate that PP2A-Pab1 plays a novel role in cytokinesis, regulating SIN activity at different levels. Pab1 is also required to activate polarized cell growth. Thus, PP2A-Pab1 may be involved in coordinating polar growth and cytokinesis.

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Section: Resultsmentioning

confidence: 99%

Antagonistic Roles of PP2A-Pab1 and Etd1 in the Control of Cytokinesis in Fission Yeast

et al. 2010

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“…The implication of Rap1GAP as a tumor suppressor was largely deduced based upon experimental results using forced overexpression of full-length Rap1GAP (60,61). In addition to its GAP domain, the Rap1GAP protein encompasses regulatory N terminus and C terminus domains (34,38), rendering it capable of exerting other functions, like regulation of heterotrimeric G z protein signaling (62) or serving as a docking site for binding partner proteins due to phosphorylation-dependent modification of its C terminus (63,64). In these experiments, we employed only the GAP domain of Rap1GAP, allowing us to confidently conclude that Rap signals mediate the PGE 2 -regulated RCC cell invasion.…”

Section: Discussionmentioning

confidence: 99%

Prostaglandin E2 Regulates Renal Cell Carcinoma Invasion through the EP4 Receptor-Rap GTPase Signal Transduction Pathway

Zhang

Frilot

et al. 2011

Journal of Biological Chemistry

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Prognosis for patients with early stage kidney cancer has improved, but the treatment options for patients with locally advanced disease and metastasis remain few. Understanding the molecular mechanisms that regulate invasion and metastasis is critical for developing successful therapies to treat these patients. Proinflammatory prostaglandin E 2 plays an important role in cancer initiation and progression via activation of cognate EP receptors that belong to the superfamily of G proteincoupled receptors. Here we report that prostaglandin E 2 promotes renal cancer cell invasion through a signal transduction pathway that encompasses EP4 and small GTPase Rap. Inactivation of Rap signaling with Rap1GAP, like inhibition of EP4 signaling with ligand antagonist or knockdown with shRNA, reduces the kidney cancer cell invasion. Human kidney cells evidence increased EP4 and decreased Rap1GAP expression levels in the malignant compared with benign samples. These results support the idea that targeted inhibition of EP4 signaling and restoration of Rap1GAP expression constitute a new strategy to control kidney cancer progression.

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“…64 and references therein). The molecular details of the negative effect of chronic inhibition of PKA activity and anchoring are new and completely unclear.…”

Section: Ratio Of Ampar-epsc To Nmdar-epsc Is Increased In Young D36mentioning

confidence: 99%

A Kinase Anchor Protein 150 (AKAP150)-associated Protein Kinase A Limits Dendritic Spine Density

Lü

Zha

Kim

et al. 2011

Journal of Biological Chemistry

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The A kinase anchor protein AKAP150 recruits the cAMPdependent protein kinase (PKA) to dendritic spines. Here we show that in AKAP150 (AKAP5) knock-out (KO) mice frequency of miniature excitatory post-synaptic currents (mEPSC) and inhibitory post-synaptic currents (mIPSC) are elevated at 2 weeks and, more modestly, 4 weeks of age in the hippocampal CA1 area versus litter mate WT mice. Linear spine density and ratio of AMPAR to NMDAR EPSC amplitudes were also increased. Amplitude and decay time of mEPSCs, decay time of mIPSCs, and spine size were unaltered. Mice in which the PKA anchoring C-terminal 36 residues of AKAP150 are deleted (D36) showed similar changes. Furthermore, whereas acute stimulation of PKA (2-4 h) increases spine density, prolonged PKA stimulation (48 h) reduces spine density in apical dendrites of CA1 pyramidal neurons in organotypic slice cultures. The data from the AKAP150 mutant mice show that AKAP150-anchored PKA chronically limits the number of spines with functional AMPARs at 2-4 weeks of age. However, synaptic transmission and spine density was normal at 8 weeks in KO and D36 mice. Thus AKAP150-independent mechanisms correct the aberrantly high number of active spines in juvenile AKAP150 KO and D36 mice during development.Dendritic spines receive most of the excitatory input in mammalian neurons (1, 2) and compartmentalize signaling that regulates the synaptic response (3, 4). Several protein kinases and phosphatases, including CaMKII, cAMP-dependent protein kinase (PKA), 3 PKC, and protein phosphatase PP2A and PP2B (calcineurin) (5) play prominent roles in synaptic plasticity. Synaptic activity translates into their activation, thereby affecting spine stability, morphology, and postsynaptic responses (6 -13). Spines are dynamically gained and lost during synaptogenesis (9, 14 -16) and in response to neuronal activity (17-19).AKAP150 is a product of the Akap5 gene in mice and is the main AKAP that recruits PKA to postsynaptic sites (20 -25). It binds with its very C terminus to the N-terminal dimerization domain of the regulatory RII subunits of PKA (26,27). It also binds PKC (28), PP2B (29,30), and the SH3-GK region of the postsynaptic scaffolding proteins SAP97 and PSD-95 (31, 32). PSD-95 binds with its PDZ domains to the C-terminal ((S/ T)X(I/V)) motif of NMDA-type glutamate receptor (NMDAR) NR2 subunits (33). PSD-95 also binds to the C terminus of stargazin (␥2) and its homologues ␥3, ␥4, and ␥8, which associate with AMPAR-type glutamate receptor (AMPAR) for postsynaptic localization in conjunction with . SAP97 directly binds to the AMPAR GluR1 subunit via a PDZ-C-terminal interaction (37) to link AKAP150 and thereby PKA, PKC,. Phosphorylation of GluR1 on Ser-845 by PKA can increase channel activity (42) and accumulation of GluR1-containing AMPAR at the postsynaptic site during hippocampal LTP (43, 44) (see also Refs. 45,46). The N terminus of AKAP150 also binds F-actin, cadherin, adenylyl cyclases, and PIP 2 and targets AKAP150 to dendritic spines and the central region binds PSD-...

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Phosphorylation of Rap1GAP, a striatally enriched protein, by protein kinase A controls Rap1 activity and dendritic spine morphology

Cited by 61 publications

References 54 publications

Antagonistic Roles of PP2A-Pab1 and Etd1 in the Control of Cytokinesis in Fission Yeast

Antagonistic Roles of PP2A-Pab1 and Etd1 in the Control of Cytokinesis in Fission Yeast

Prostaglandin E2 Regulates Renal Cell Carcinoma Invasion through the EP4 Receptor-Rap GTPase Signal Transduction Pathway

A Kinase Anchor Protein 150 (AKAP150)-associated Protein Kinase A Limits Dendritic Spine Density

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