Liprins, a Family of LAR Transmembrane Protein-tyrosine Phosphatase-interacting Proteins

Serra-Pagès, Carles; Medley, Quintus G.; Tang, May; Hart, Anne C.; Streuli, Michel

doi:10.1074/jbc.273.25.15611

Cited by 266 publications

(328 citation statements)

References 38 publications

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“…Previous studies also have shown that in mammalian cells, LAR and Liprin-␣ colocalize at focal adhesion contacts (18), but in the absence of cotransfected Liprin-␣, LAR is uniformly distributed throughout the plasma membrane (23). In contrast to Liprin-␣ acts partially in parallel to LAR in R7 targeting.…”

Section: Discussionmentioning

confidence: 92%

“…In cultured hippocampal neurons, Liprin-␣ promotes glutamate receptor targeting to synapses (21,22). The observations that human Liprin-␣2 promotes clustering of LAR within the plasma membrane in COS cells, and that SYD-2 and the C. elegans LAR homologue PTP-3 regulate each other's localization along the nerve cord, suggest that localization also may be the mechanism by which Liprin-␣ influences LAR function (23,24).…”

mentioning

confidence: 95%

“…In C. elegans syd-2 mutants, the LAR homologue PTP-3 fails to cluster at synapses (24), and in cultured mammalian cells, Liprin-␣ promotes the localization of LAR to focal adhesions (18,23). We therefore analyzed the intracellular distribution of LAR in Liprin-␣ oos mutant photoreceptors.…”

Section: Liprin-␣ Is Not Required For Lar Localization In Photoreceptmentioning

confidence: 99%

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Liprin-α has LAR-independent functions in R7 photoreceptor axon targeting

Hofmeyer

Maurel-Zaffran

Sink

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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In the Drosophila visual system, the color-sensing photoreceptors R7 and R8 project their axons to two distinct layers in the medulla. Loss of the receptor tyrosine phosphatase LAR from R7 photoreceptors causes their axons to terminate prematurely in the R8 layer. Here we identify a null mutation in the Liprin-␣ gene based on a similar R7 projection defect. Liprin-␣ physically interacts with the inactive D2 phosphatase domain of LAR, and this domain is also essential for R7 targeting. However, another LAR-dependent function, egg elongation, requires neither Liprin-␣ nor the LAR D2 domain. Although human and Caenorhabditis elegans Liprin-␣ proteins have been reported to control the localization of LAR, we find that LAR localizes to focal adhesions in Drosophila S2R؉ cells and to photoreceptor growth cones in vivo independently of Liprin-␣. In addition, Liprin-␣ overexpression or loss of function can affect R7 targeting in the complete absence of LAR. We conclude that Liprin-␣ does not simply act by regulating LAR localization but also has LAR-independent functions. receptor tyrosine phosphatase ͉ visual system ͉ Drosophila T he color-sensitive photoreceptors of the Drosophila visual system, R7 and R8, provide a simple system in which to study layer-specific axon targeting. Whereas the outer photoreceptors R1-R6 project their axons to the lamina, R7 and R8 project to the medulla, where R8 terminates in the more superficial M3 layer and R7 in the deeper M6 layer. This targeting occurs in two stages, with both R7 and R8 growth cones pausing in separate temporary layers before proceeding to their final positions (1). Several genes are known to contribute to the establishment of the R7 and R8 projection pattern. The transcription factor Runt is expressed in R7 and R8, and its misexpression is sufficient to target R2 and R5 to the medulla, suggesting that it controls the choice of optic neuropil (2). Endogenous expression of the homophilic cell adhesion molecule Capricious (Caps) in R8 or its ectopic expression in R7 directs these photoreceptors to terminate in the Caps-positive M3 layer (3). The transmembrane cadherin Flamingo (Fmi) is required for R8 targeting (4, 5), whereas loss of either N-cadherin (Ncad) (6) or one of the receptor protein tyrosine phosphatases (RPTPs), PTP69D (7) or LAR (8, 9), causes R7 to terminate inappropriately in the R8 layer.Other functions of LAR include axonal patterning of photoreceptors R1-R6 (9) and embryonic motor neurons (10, 11), synapse morphogenesis at the larval neuromuscular junction (NMJ) (12), and polarization of actin filaments in the follicle cells surrounding the oocyte, which promotes egg elongation along the anterior-posterior axis (13,14). It is unclear how LAR and other RPTPs signal within the cell to induce the cytoskeletal rearrangements that mediate these functions. Trio, a guanine nucleotide exchange factor for Rac (15), and Enabled (Ena), which regulates actin polymerization (16), show genetic interactions with LAR in both R7 targeting (8) and motor axon guidance ...

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Section: Discussionmentioning

confidence: 92%

mentioning

confidence: 95%

Section: Liprin-␣ Is Not Required For Lar Localization In Photoreceptmentioning

confidence: 99%

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Liprin-α has LAR-independent functions in R7 photoreceptor axon targeting

Hofmeyer

Maurel-Zaffran

Sink

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…Liprin-a binds to receptor protein tyrosine phosphatase (Dlar), which suggests that liprin-a3 and Dlar are involved in the formation of presynaptic active zones. 82 MALS-CASK-Mint 1 complex occurs pre-and postsynaptically and has a distinct role in both the locations. 83,84 Postsynaptically MALS is known to bind to NMDA receptors and also involved in the transport of NMDA receptor vesicle along microtubules.…”

Section: Discussionmentioning

confidence: 99%

Cytosolic proteomic alterations in the nucleus accumbens of cocaine overdose victims

2006

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Chronic cocaine use in humans and animal models is known to lead to pronounced alterations in neuronal function in the nucleus accumbens (NAc), a brain region associated with drug reinforcement. Two-dimensional gel electrophoresis was used to compare protein alterations in the NAc between cocaine overdose (COD) victims (n = 10) and controls (n = 10). Following image normalization, spots with significantly differential image intensities (P < 0.05) were identified, excised, trypsin digested and analyzed by matrix-assisted laser desorption ionization-time of flight-time of flight. A total of 1407 spots were found to be present in a minimum of five subjects per group and the intensity of 18 spots was found to be differentially abundant between the groups, leading to positive identification of 15 proteins by peptide mass fingerprinting (PMF). Of an additional 37 protein spots that were constitutively expressed, 32 proteins were positively identified by PMF. Increased proteins in COD included b-tubulin, liprin-a3 and neuronal enolase, whereas decreased proteins included parvalbumin, ATP synthase b-chain and peroxiredoxin 2. The present data provide a preliminary protein profile of COD, suggesting the involvement of novel proteins and pathways in the expression of this complex disease. Additional studies are warranted to further characterize alterations in the differentially regulated proteins. Understanding the coordinated involvement of multiple proteins in cocaine abuse provides insight into the molecular basis of the disease and offers new targets for pharmacotherapeutic intervention for drug abuse-related disorders.

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“…A proline-rich sequence in the linker between the C 2 A and C 2 B domain interacts with the SH3 domain of brain-specific adaptor proteins called RIM-BPs (4) that have been implicated in Ca 2ϩ -channel regulation (10). The C-terminal C 2 B domain binds to ␣-liprins (6), putative adaptor proteins of the active zone that were shown in invertebrates to be essential for regulating active zone size (11)(12)(13), and to synaptotagmin 1, which in turn regulates release (6,14). RIMs thus behave like a molecular scaffold that tethers multiple synaptic proteins.…”

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confidence: 99%

A family of RIM-binding proteins regulated by alternative splicing: Implications for the genesis of synaptic active zones

Wang

Liu

Biederer

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

232

276

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RIMs are presynaptic active zone proteins that regulate neurotransmitter release. We describe two related genes that encode proteins with identical C-terminal sequences that bind to the conserved PDZ domain of RIMs via an unusual PDZ-binding motif. These proteins were previously reported separately as ELKS, Rab6-interacting protein 2, and CAST, leading us to refer to them by the acronym ERC. Alternative splicing of the C terminus of ERC1 generates a longer ERC1a variant that does not bind to RIMs and a shorter ERC1b variant that binds to RIMs, whereas the C terminus of ERC2 is synthesized only in a single RIM-binding variant. ERC1a is expressed ubiquitously as a cytosolic protein outside of brain; ERC1b is detectable only in brain, where it is both a cytosolic protein and an insoluble active zone component; and ERC2 is brain-specific but exclusively localized to active zones. Only brainspecific ERCs bind to RIMs, but both ubiquitous and brain-specific ERCs bind to Rab6, a GTP-binding protein involved in membrane traffic at the Golgi complex. ERC1a and ERC1b͞2 likely perform similar functions at distinct localizations, indicating unexpected connections between nonneuronal membrane traffic at the Golgi complex executed via Rab6 and neuronal membrane traffic at the active zone executed via RIMs. R IM1␣ and -2␣ are multidomain adaptor proteins that were discovered as putative effectors for Rab3, a synaptic vesicle protein that binds GTP and regulates neurotransmitter release (1-4). RIMs are composed of an N-terminal Zn 2ϩ -finger domain, a central PDZ domain, and C-terminal C 2 A and C 2 B domains (3, 4). The binding of RIMs to Rab3 and the localization of RIM1␣ to presynaptic active zones suggested a function in neurotransmitter release, which was confirmed by genetic experiments in Caenorhabditis elegans and mice (5-7). Deletion of RIM1␣ in mice caused distinct phenotypes in different types of synapses. In excitatory synapses capable of N-methyl-Daspartate (NMDA)-dependent long-term potentiation (e.g., Schaffer collateral͞commissural fiber synapses in the CA1 region of the hippocampus) and in inhibitory synapses, deletion of RIM1␣ decreased the neurotransmitter release probability in response to Ca 2ϩ influx, leading to a decline in synaptic transmission and changes in short-term synaptic plasticity (6). In excitatory synapses that lack NMDA-dependent long-term potentiations but experience protein kinase A-dependent longterm potentiation (e.g., mossy fiber synapses in the CA3 region of the hippocampus), deletion of RIM1␣ had no detectable effect on acute neurotransmitter release but prevented protein kinase A-dependent potentiation (7). Although these results confirmed an important role for RIM1␣ and, by extension, RIM2␣, in presynaptic function, the spectrum of mutant phenotypes suggests that this role is incompletely understood.It is likely that RIMs regulate release by interacting with other proteins. Several binding partners were identified. The Nterminal Zn 2ϩ -finger domain of RIM1␣ directly binds to Rab3 [w...

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Liprins, a Family of LAR Transmembrane Protein-tyrosine Phosphatase-interacting Proteins

Cited by 266 publications

References 38 publications

Liprin-α has LAR-independent functions in R7 photoreceptor axon targeting

Liprin-α has LAR-independent functions in R7 photoreceptor axon targeting

Cytosolic proteomic alterations in the nucleus accumbens of cocaine overdose victims

A family of RIM-binding proteins regulated by alternative splicing: Implications for the genesis of synaptic active zones

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