Functions of the Ectodomain and Cytoplasmic Tyrosine Phosphatase Domains of Receptor Protein Tyrosine Phosphatase Dlar In Vivo

Krueger, Neil X.; Reddy, R. Sreekantha; Johnson, Karl G.; Bateman, Jack R.; Kaufmann, Nancy; Scalice, D.; Vactor, David Van; Saito, Haruo

doi:10.1128/mcb.23.19.6909-6921.2003

Cited by 26 publications

(37 citation statements)

References 53 publications

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“…These results show that LAR function in R7 targeting is independent of its phosphatase activity, but requires a conformation dependent on the wedge domain. ectopically expressed (12), but not to restore viability to Lar mutants (8). In the absence of LAR, most R7 photoreceptor axons terminate at the more superficial R8 layer (4, 6) ( Fig.…”

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confidence: 95%

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confidence: 99%

“…The membrane-distal D2 domains of such RPTPs show no phosphatase activity on artificial substrates in vitro (7)(8)(9). Nevertheless, the LAR D2 domain is essential for R7 targeting, where it may act by recruiting the scaffolding protein Liprin-␣ (10) or regulating the activity of the D1 domain (8). An important class of ligands for type IIa RPTPs are heparan sulfate proteoglycans (HSPGs) such as Agrin and Collagen XVIII, which bind to PTP (11), and Syndecan (Sdc) and Dally-like (Dlp), which control the activity of Drosophila LAR in motor neurons (12,13).…”

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confidence: 99%

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The receptor protein tyrosine phosphatase LAR promotes R7 photoreceptor axon targeting by a phosphatase-independent signaling mechanism

Hofmeyer

Treisman

2009

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

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Receptor protein tyrosine phosphatases (RPTPs) control many aspects of nervous system development. At the Drosophila neuromuscular junction (NMJ), regulation of synapse growth and maturation by the RPTP LAR depends on catalytic phosphatase activity and on the extracellular ligands Syndecan and Dally-like. We show here that the function of LAR in controlling R7 photoreceptor axon targeting in the visual system differs in several respects. The extracellular domain of LAR important for this process is distinct from the domains known to bind Syndecan and Dally-like, suggesting the involvement of a different ligand. R7 targeting does not require LAR phosphatase activity, but instead depends on the phosphatase activity of another RPTP, PTP69D. In addition, a mutation that prevents dimerization of the intracellular domain of LAR interferes with its ability to promote R7 targeting, although it does not disrupt phosphatase activity or neuromuscular synapse growth. We propose that LAR function in R7 is independent of its phosphatase activity, but requires structural features that allow dimerization and may promote the assembly of downstream effectors.synapse ͉ neuromuscular junctions ͉ dimerization ͉ wedge R eceptor protein tyrosine phosphatases (RPTPs) are required for nervous system development in both vertebrates and invertebrates (1). Of the six Drosophila RPTPs, Leukocyte antigen-related (LAR) has been studied in most detail due to its non-redundant role in several developmental processes. In Lar mutant embryos, motor neurons in the intersegmental nerve b (ISNb) fail to innervate the appropriate muscles and aberrantly track along the ISN (2). LAR has two distinct functions at the synapses formed by larval motor neurons on their target muscles. Synapse size as defined by the number of synaptic boutons present at these larval neuromuscular junctions (NMJs) is proportional to Lar dosage; and LAR controls active zone morphogenesis and thus synaptic strength (3). In the visual system, LAR enables photoreceptor axons to establish connections to the correct synaptic partners. Photoreceptors R1-R6 project into the lamina, where the axons from a single ommatidium defasciculate and connect to six different laminar cartridges; this defasciculation requires Lar (4). Photoreceptors R7 and R8, which mediate color vision, project beyond the lamina to terminate in two distinct layers of the medulla, R8 in M3 and R7 in the deeper M6 layer (5). In Lar mutants, most R7 axons terminate inappropriately in M3, the same layer as R8 (4, 6).LAR and its vertebrate homologues PTP and PTP␦ are type IIa RPTPs, which have two intracellular phosphatase domains (D1 and D2) and extracellular Ig (Ig) and fibronectin type III (FNIII) domains. The membrane-distal D2 domains of such RPTPs show no phosphatase activity on artificial substrates in vitro (7-9). Nevertheless, the LAR D2 domain is essential for R7 targeting, where it may act by recruiting the scaffolding protein Liprin-␣ (10) or regulating the activity of the D1 domain (8). An important class...

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The receptor protein tyrosine phosphatase LAR promotes R7 photoreceptor axon targeting by a phosphatase-independent signaling mechanism

Hofmeyer

Treisman

2009

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

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“…2D). Third, the D2 domain is essential for LAR function in R7 targeting, because its absence in either the LAR bypass truncation allele (27,28) or a deleted LAR rescue construct (28) resulted in a strong R7 projection defect (Fig. 2L).…”

Section: A Direct Interaction Between Lar and Liprin-␣ Is Required Fomentioning

confidence: 99%

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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“…Recent studies have conveyed the importance of Ig domains in the extracellular segments of RPTP-LAR and PTP, which are in a different structural class from PTP. In Drosophila, the three Ig domains of PTP-LAR have been shown to be important for survival (38). The N-terminal Ig domain of PTP mediates binding to heparin sulfate proteoglycans and may be critical in targeting the phosphatase to sites of cell-matrix interaction (39).…”

Section: Discussionmentioning

confidence: 99%

The Conserved Immunoglobulin Domain Controls the Subcellular Localization of the Homophilic Adhesion Receptor Protein-tyrosine Phosphatase μ

Vecchio

Tonks

2005

Journal of Biological Chemistry

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The receptor protein-tyrosine phosphatase (PTP) is a homophilic adhesion protein thought to regulate cell-cell adhesion in the vascular endothelium through dephosphorylation of cell junction proteins. In subconfluent cell cultures, PTP resides in an intracellular membrane pool; however, as culture density increases and cell contacts form, the phosphatase localizes to sites of cell-cell contact, and its expression level increases. These characteristics of PTP, which are consistent with a role in cell-cell adhesion, suggest that control of subcellular localization is an important mechanism to regulate the function of this phosphatase. To gain a better understanding of how PTP is regulated, we ex- The physical interactions of individual cells with the local environment is critical to the control of their growth, differentiation, and fate within a multicellular organism. These responses are initiated by cell adhesion receptors, which bind either homophilic or heterophilic ligands on apposing cells or the extracellular matrix. A critical aspect in the cellular response to these interactions is reversible protein tyrosine phosphorylation of cell junction-associated proteins (1, 2). In fact, the bulk of the tyrosine-phosphorylated cellular proteins are localized to sites of cell-cell and cell-extracellular matrix adhesion. Several protein-tyrosine kinases and phosphatases have been implicated in the regulation of cell adhesion (3-6). In particular, receptor protein-tyrosine phosphatases (RPTPs),

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Functions of the Ectodomain and Cytoplasmic Tyrosine Phosphatase Domains of Receptor Protein Tyrosine Phosphatase Dlar In Vivo

Cited by 26 publications

References 53 publications

The receptor protein tyrosine phosphatase LAR promotes R7 photoreceptor axon targeting by a phosphatase-independent signaling mechanism

The receptor protein tyrosine phosphatase LAR promotes R7 photoreceptor axon targeting by a phosphatase-independent signaling mechanism

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

The Conserved Immunoglobulin Domain Controls the Subcellular Localization of the Homophilic Adhesion Receptor Protein-tyrosine Phosphatase μ

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