RESUMO
Type IIa receptor tyrosine phosphatases (RPTPs) play pivotal roles in neuronal network formation. It is emerging that the interactions of RPTPs with glycans, i.e., chondroitin sulfate (CS) and heparan sulfate (HS), are critical for their functions. We highlight here the significance of these interactions in axon regeneration and synaptogenesis. For example, PTPσ, a member of type IIa RPTPs, on axon terminals is monomerized and activated by the extracellular CS deposited in neural injuries, dephosphorylates cortactin, disrupts autophagy flux, and consequently inhibits axon regeneration. In contrast, HS induces PTPσ oligomerization, suppresses PTPσ phosphatase activity, and promotes axon regeneration. PTPσ also serves as an organizer of excitatory synapses. PTPσ and neurexin bind one another on presynapses and further bind to postsynaptic leucine-rich repeat transmembrane protein 4 (LRRTM4). Neurexin is now known as a heparan sulfate proteoglycan (HSPG), and its HS is essential for the binding between these three molecules. Another HSPG, glypican 4, binds to presynaptic PTPσ and postsynaptic LRRTM4 in an HS-dependent manner. Type IIa RPTPs are also involved in the formation of excitatory and inhibitory synapses by heterophilic binding to a variety of postsynaptic partners. We also discuss the important issue of possible mechanisms coordinating axon extension and synapse formation.
Assuntos
Axônios/metabolismo , Regeneração Nervosa , Polissacarídeos/fisiologia , Proteínas Tirosina Fosfatases Semelhantes a Receptores/fisiologia , Sinapses/metabolismo , Animais , Axônios/fisiologia , Humanos , Polissacarídeos/metabolismo , Proteínas Tirosina Fosfatases Semelhantes a Receptores/metabolismo , Sinapses/fisiologiaRESUMO
Stem cell compartments in metazoa get regulated by systemic factors as well as local stem cell niche-derived factors. However, the mechanisms by which systemic signals integrate with local factors in maintaining tissue homeostasis remain unclear. Employing the Drosophila lymph gland, which harbors differentiated blood cells, and stem-like progenitor cells and their niche, we demonstrate how a systemic signal interacts and harmonizes with local factor/s to achieve cell type-specific tissue homeostasis. Our genetic analyses uncovered a novel function of Lar, a receptor protein tyrosine phosphatase. Niche-specific loss of Lar leads to upregulated insulin signaling, causing increased niche cell proliferation and ectopic progenitor differentiation. Insulin signaling assayed by PI3K activation is downregulated after the second instar larval stage, a time point that coincides with the appearance of Lar in the hematopoietic niche. We further demonstrate that Lar physically associates with InR and serves as a negative regulator for insulin signaling in the Drosophila larval hematopoietic niche. Whether Lar serves as a localized invariable negative regulator of systemic signals such as insulin in other stem cell niches remains to be explored.
Assuntos
Proteínas de Drosophila/fisiologia , Hematopoese/genética , Células-Tronco Hematopoéticas/citologia , Homeostase/genética , Insulina/metabolismo , Proteínas Tirosina Fosfatases Semelhantes a Receptores/fisiologia , Nicho de Células-Tronco/genética , Animais , Animais Geneticamente Modificados , Diferenciação Celular/genética , Proliferação de Células/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/embriologia , Drosophila melanogaster/genética , Embrião não Mamífero , Células-Tronco Hematopoéticas/fisiologia , Ligação Proteica , Receptores Proteína Tirosina Quinases/metabolismo , Receptor de Insulina/metabolismo , Proteínas Tirosina Fosfatases Semelhantes a Receptores/metabolismo , Transdução de Sinais/fisiologiaRESUMO
Sensory dendrite morphogenesis is directed by intrinsic and extrinsic factors. The extracellular environment plays instructive roles in patterning dendrite growth and branching. However, the molecular mechanism is not well understood. In Caenorhabditis elegans, the proprioceptive neuron PVD forms highly branched sensory dendrites adjacent to the hypodermis. We report that receptor tyrosine phosphatase CLR-1 functions in the hypodermis to pattern the PVD dendritic branches. Mutations in clr-1 lead to loss of quaternary branches, reduced secondary branches and increased ectopic branches. CLR-1 is necessary for the dendrite extension but not for the initial filopodia formation. Its role is dependent on the intracellular phosphatase domain but not the extracellular adhesion domain, indicating that it functions through dephosphorylating downstream factors but not through direct adhesion with neurons. Genetic analysis reveals that clr-1 also functions in parallel with SAX-7/DMA-1 pathway to control PVD primary dendrite development. We provide evidence of a new environmental factor for PVD dendrite morphogenesis.
Assuntos
Proteínas de Caenorhabditis elegans/fisiologia , Dendritos/metabolismo , Proteínas Tirosina Fosfatases Semelhantes a Receptores/fisiologia , Pele/embriologia , Animais , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/metabolismo , Derme/embriologia , Proteínas de Fluorescência Verde/metabolismo , Mutação , Moléculas de Adesão de Célula Nervosa/metabolismo , Neurônios/metabolismo , Fosforilação , Estrutura Terciária de Proteína , Pseudópodes/metabolismo , Células Receptoras Sensoriais/metabolismo , TransgenesRESUMO
Protein tyrosine phosphatases (PTPs) play an important role in regulating cell signaling events in coordination with tyrosine kinases to control cell proliferation, apoptosis, survival, migration, and invasion. Receptor-type protein tyrosine phosphatases (PTPRs) are a subgroup of PTPs that share a transmembrane domain with resulting similarities in function and target specificity. In this review, we summarize genetic and epigenetic alterations including mutation, deletion, amplification, and promoter methylation of PTPRs in cancer and consider the consequences of PTPR alterations in different types of cancers. We also summarize recent developments using PTPRs as prognostic or predictive biomarkers and/or direct targets. Increased understanding of the role of PTPRs in cancer may provide opportunities to improve therapeutic approaches.
Assuntos
Neoplasias/enzimologia , Proteínas Tirosina Fosfatases Semelhantes a Receptores/fisiologia , Apoptose , Proliferação de Células , Sobrevivência Celular , Humanos , Invasividade Neoplásica , Proteínas Tirosina Fosfatases Semelhantes a Receptores/genéticaRESUMO
Establishment of synaptic connections in the neuropils of the developing nervous system requires the coordination of specific neurite-neurite interactions (i.e., axon-axon, dendrite-dendrite and axon-dendrite interactions). The molecular mechanisms underlying coordination of neurite-neurite interactions for circuit assembly are incompletely understood. In this report, we identify a novel Ig superfamily transmembrane protein that we named Borderless (Bdl), as a novel regulator of neurite-neurite interactions in Drosophila. Bdl induces homotypic cell-cell adhesion in vitro and mediates neurite-neurite interactions in the developing visual system. Bdl interacts physically and genetically with the Ig transmembrane protein Turtle, a key regulator of axonal tiling. Our results also show that the receptor tyrosine phosphatase leukocyte common antigen-related protein (LAR) negatively regulates Bdl to control synaptic-layer selection. We propose that precise regulation of Bdl action coordinates neurite-neurite interactions for circuit formation in Drosophila.
Assuntos
Comunicação Celular/genética , Proteínas de Drosophila/fisiologia , Proteínas de Membrana/fisiologia , Rede Nervosa/fisiologia , Vias Visuais/fisiologia , Animais , Regulação para Baixo/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/enzimologia , Drosophila melanogaster/genética , Feminino , Subunidades de Imunoglobulinas/genética , Imunoglobulinas/genética , Imunoglobulinas/fisiologia , Masculino , Proteínas de Membrana/genética , Mutação/genética , Rede Nervosa/enzimologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Neuritos/fisiologia , Proteínas Tirosina Fosfatases Semelhantes a Receptores/genética , Proteínas Tirosina Fosfatases Semelhantes a Receptores/fisiologia , Vias Visuais/enzimologiaRESUMO
CD45 is a receptor-like tyrosine phosphatase that positively regulates BCR signaling by dephosphorylating the inhibitory tyrosine of the Src family kinases. We showed previously that a single point mutation, E613R, introduced into the cytoplasmic membrane-proximal "wedge" domain of CD45 is sufficient to drive a lupus-like autoimmune disease on a susceptible genetic background. To clarify the molecular mechanism of this disease, we took advantage of a unique allelic series of mice in which the expression of CD45 is varied across a broad range. Although both E613R B cells and those with supraphysiologic CD45 expression exhibited hyperresponsive BCR signaling, they did so by opposite regulation of the Src family kinase Lyn. We demonstrated that the E613R allele of CD45 does not function as a hyper- or hypomorphic allele but rather alters the substrate specificity of CD45 for Lyn. Despite similarly enhancing BCR signaling, only B cells with supraphysiologic CD45 expression became anergic, whereas only mice harboring the E613R mutation developed frank autoimmunity on a susceptible genetic background. We showed that selective impairment of a Lyn-dependent negative-regulatory circuit in E613R B cells drove autoimmunity in E613R mice. This demonstrates that relaxing negative regulation of BCR signaling, rather than enhancing positive regulation, is critical for driving autoimmunity in this system.
Assuntos
Subpopulações de Linfócitos B/enzimologia , Subpopulações de Linfócitos B/imunologia , Tolerância Imunológica , Antígenos Comuns de Leucócito/fisiologia , Proteínas Tirosina Fosfatases Semelhantes a Receptores/fisiologia , Alelos , Animais , Subpopulações de Linfócitos B/citologia , Variação Genética/imunologia , Tolerância Imunológica/genética , Antígenos Comuns de Leucócito/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Mutantes , Camundongos Transgênicos , Estrutura Terciária de Proteína/genética , Proteínas Tirosina Fosfatases Semelhantes a Receptores/deficiência , Proteínas Tirosina Fosfatases Semelhantes a Receptores/genética , Especificidade por Substrato/genética , Especificidade por Substrato/imunologia , Quinases da Família src/genética , Quinases da Família src/metabolismoRESUMO
The multiprotein complexes that receive and transmit axon pathfinding cues during development are essential to circuit generation. Here, we identify and characterize the Drosophila sterile α-motif (SAM) domain-containing protein Caskin, which shares homology with vertebrate Caskin, a CASK [calcium/calmodulin-(CaM)-activated serine-threonine kinase]-interacting protein. Drosophila caskin (ckn) is necessary for embryonic motor axon pathfinding and interacts genetically and physically with the leukocyte common antigen-related (Lar) receptor protein tyrosine phosphatase. In vivo and in vitro analyses of a panel of ckn loss-of-function alleles indicate that the N-terminal SAM domain of Ckn mediates its interaction with Lar. Like Caskin, Liprin-α is a neuronal adaptor protein that interacts with Lar via a SAM domain-mediated interaction. We present evidence that Lar does not bind Caskin and Liprin-α concurrently, suggesting they may assemble functionally distinct signaling complexes on Lar. Furthermore, a vertebrate Caskin homolog interacts with LAR family members, arguing that the role of ckn in Lar signal transduction is evolutionarily conserved. Last, we characterize several ckn mutants that retain Lar binding yet display guidance defects, implying the existence of additional Ckn binding partners. Indeed, we identify the SH2/SH3 adaptor protein Dock as a second Caskin-binding protein and find that Caskin binds Lar and Dock through distinct domains. Furthermore, whereas ckn has a nonredundant function in Lar-dependent signaling during motor axon targeting, ckn and dock have overlapping roles in axon outgrowth in the CNS. Together, these studies identify caskin as a neuronal adaptor protein required for axon growth and guidance.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Axônios/fisiologia , Proteínas de Drosophila/genética , Proteínas de Drosophila/fisiologia , Neurônios Motores/fisiologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Proteínas Tirosina Fosfatases Semelhantes a Receptores/fisiologia , Transdução de Sinais/fisiologia , Alelos , Animais , Animais Geneticamente Modificados , DNA Complementar/genética , Drosophila , Vias Eferentes/citologia , Vias Eferentes/fisiologia , Metanossulfonato de Etila/farmacologia , Glutationa Transferase/metabolismo , Imuno-Histoquímica , Imunoprecipitação , Mutagênese , Mutagênicos/farmacologia , Mutação/genética , Mutação/fisiologia , Plasmídeos/genética , Ligação Proteica , RNA/biossíntese , RNA/genética , Proteínas Tirosina Fosfatases Semelhantes a Receptores/genética , TransfecçãoRESUMO
Liprin-α1 to liprin-α4 constitute a family of cytoplasmic proteins, which have been found in various multiprotein complexes. For liprin-α1 roles in synapse formation and cell spreading were described but other liprin family members are not well characterized. We show here that liprin-α4 is upregulated in human clear cell renal cell carcinomas (RCC) as compared to normal kidney tissue. Liprin-α4 expression is downregulated by the von Hippel-Lindau tumor suppressor (VHL) and upregulated by hypoxia in RCC cell lines. The liprin-α4 gene promoter is directly activated by binding of the hypoxia-inducible factor 1α (HIF-1α) to HRE consensus binding sites as shown by reporter assays and chromatin immunoprecipitations. RNAi mediated knockdown of liprin-α4 leads to reduced E-cadherin and ß-catenin levels at cell junctions and to dissociation of epithelial cell contacts. Our data describe for the first time liprin-α4 as a hypoxia-induced gene potentially involved in cell-cell adhesion.
Assuntos
Comunicação Celular , Hipóxia , Proteínas Tirosina Fosfatases Semelhantes a Receptores/fisiologia , Caderinas/análise , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Adesão Celular , Linhagem Celular Tumoral , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Rim/citologia , Rim/metabolismo , Regiões Promotoras Genéticas/genética , Proteínas Tirosina Fosfatases Semelhantes a Receptores/genética , Regulação para Cima/genética , beta Catenina/análiseRESUMO
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.
Assuntos
Axônios/fisiologia , Proteínas de Drosophila/fisiologia , Drosophila melanogaster/crescimento & desenvolvimento , Junção Neuromuscular/crescimento & desenvolvimento , Células Fotorreceptoras de Invertebrados/fisiologia , Proteínas Tirosina Fosfatases Semelhantes a Receptores/fisiologia , Animais , Axônios/enzimologia , Proteínas de Drosophila/genética , Drosophila melanogaster/enzimologia , Junção Neuromuscular/enzimologia , Células Fotorreceptoras de Invertebrados/enzimologia , Proteínas Tirosina Fosfatases Semelhantes a Receptores/genética , Transdução de SinaisRESUMO
The diaphanous gene is the founding member of a family of Diaphanous-related formin proteins (DRFs). We identified diaphanous in a screen for genes that are necessary for the normal growth and stabilization of the Drosophila neuromuscular junction (NMJ). Here, we demonstrate that diaphanous mutations perturb synaptic growth at the NMJ. Diaphanous protein is present both presynaptically and postsynaptically. However, genetic rescue experiments in combination with additional genetic interaction experiments support the conclusion that dia is necessary presynaptically for normal NMJ growth. We then document defects in both the actin and microtubule cytoskeletons in dia mutant nerve terminals. In so doing, we define and characterize a population of dynamic pioneer microtubules within the NMJ that are distinct from the bundled core of microtubules identified by the MAP1b-like protein Futsch. Defects in both synaptic actin and dynamic pioneer microtubules are correlated with impaired synaptic growth in dia mutants. Finally, we present genetic evidence that Dia functions downstream of the presynaptic receptor tyrosine phosphatase Dlar and the Rho-type GEF (guanine nucleotide exchange factor) trio to control NMJ growth. Based on the established function of DRFs as Rho-GTPase-dependent regulators of the cell cytoskeleton, we propose a model in which Diaphanous links receptor tyrosine phosphatase signaling at the plasma membrane to growth-dependent modulation of the synaptic actin and microtubule cytoskeletons.
Assuntos
Actinas/fisiologia , Proteínas de Transporte/fisiologia , Proteínas de Drosophila/fisiologia , Proteínas dos Microfilamentos/fisiologia , Microtúbulos/fisiologia , Proteínas Tirosina Fosfatases Semelhantes a Receptores/fisiologia , Sinapses/fisiologia , Actinas/genética , Animais , Animais Geneticamente Modificados , Proteínas de Transporte/genética , Células Cultivadas , Drosophila , Proteínas de Drosophila/genética , Proteínas Fetais/genética , Proteínas Fetais/fisiologia , Forminas , Proteínas dos Microfilamentos/genética , Microtúbulos/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Junção Neuromuscular/genética , Junção Neuromuscular/crescimento & desenvolvimento , Proteínas Nucleares/genética , Proteínas Nucleares/fisiologia , Proteínas Tirosina Fosfatases Semelhantes a Receptores/genética , Transdução de Sinais/fisiologiaAssuntos
Rede Nervosa/fisiologia , Proteínas Tirosina Fosfatases Semelhantes a Receptores/fisiologia , Retina/fisiologia , Animais , Galinhas , Efrinas , Ligantes , Proteínas Tirosina Fosfatases Semelhantes a Receptores/química , Proteínas Tirosina Fosfatases Semelhantes a Receptores/classificação , Receptores da Família Eph , Retina/anatomia & histologiaRESUMO
Receptor tyrosine phosphatases (RPTPs) are required for axon guidance during embryonic development in Drosophila. Here we examine the roles of four RPTPs during development of the larval mushroom body (MB). MB neurons extend axons into parallel tracts known as the peduncle and lobes. The temporal order of neuronal birth is reflected in the organization of axons within these tracts. Axons of the youngest neurons, known as core fibers, extend within a single bundle at the center, while those of older neurons fill the outer layers. RPTPs are selectively expressed on the core fibers of the MB. Ptp10D and Ptp69D regulate segregation of the young axons into a single core bundle. Ptp69D signaling is required for axonal extension beyond the peduncle. Lar and Ptp69D are necessary for the axonal branching decisions that create the lobes. Avoidance of the brain midline by extending medial lobe axons involves signaling through Lar.