RPTPα is required for rigidity-dependent inhibition of extension and differentiation of hippocampal neurons

Kostić, Ana; Sap, Jan; Sheetz, Michael P.

doi:10.1242/jcs.009852

Cited by 97 publications

(106 citation statements)

References 83 publications

(120 reference statements)

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“…In mammals prepro-GnRH-II is encoded by the GnRH2 gene which is physically linked to the genes PTPRA (∼5–6 kb upstream), which encodes a receptor-type tyrosine-protein phosphatase involved in neural differentiation [51] and MRPS26 (∼0.3 kb downstream), which encodes the mitochondrial ribosome protein S26. These genes also flank GnRH2 in non-mammalian vertebrates [36].…”

Section: Resultsmentioning

confidence: 99%

Retention and Silencing of Prepro-GnRH-II and Type II GnRH Receptor Genes in Mammals

Stewart¹,

Katz²,

Millar³

et al. 2009

Neuroendocrinology

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The decapeptide hypothalamic-pituitary gonadotrophin-releasing hormone (GnRH)-I and the type I GnRH receptor drive the reproductive hormonal cascade in mammals by stimulating synthesis and secretion of luteinising hormone (LH) and follicle stimulating hormone (FSH). Mammals possess a second GnRH system composed of a related hormone, GnRH-II (differing from GnRH-I by three amino acid residues), and the type II GnRH receptor. In many mammalian species, one or both of the GnRH-II system genes are disrupted or deleted, rendering their products non-functional. This includes humans who possess a gene encoding GnRH-II but lack a functional type II GnRH receptor. Here we examined the genes encoding prepro-GnRH-II (GnRH2) and the type II GnRH receptor (GnRHR2) in more than 20 mammalian species, encompassing 10 orders, to determine whether they encode functional proteins. The structural organisation of both genes in most mammalian genome sequence assemblies was poorly annotated or incompletely described. Our findings show significant variation in the DNA sequence conservation and functional status of each gene, even between closely related species. Prepro-GnRH-II was functionally compromised in 12/22 species and the type II GnRH receptor gene was disrupted in 14/22 species. Retention of large sections of each gene in most mammalian genomes suggests that mammalian ancestors had a functional GnRH-II system. Gene disruptions were due to a spectrum of mutations which must have occurred independently after the evolutionary divergence of mammals from ancestral animals. The genetic information will be useful for understanding the physiological role of the GnRH-II system and establishing animal models for functional studies.

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Section: Resultsmentioning

confidence: 99%

Retention and Silencing of Prepro-GnRH-II and Type II GnRH Receptor Genes in Mammals

Stewart¹,

Katz²,

Millar³

et al. 2009

Neuroendocrinology

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“…Thus, we suggest that localized (1-2 μm) contractions recruit active myosin until the matrix is displaced by a defined amount (very rigid surfaces would exceed the range of the system). The loss of RPTPα reduces the activation of Src family kinases that are critical for rigidity sensing (26)(27)(28) and reduces the displacement in the local contractions. Thus, we suggest that the Src family kinases are coupled with localized contraction and force sensing that are integral parts of the rigidity sensing process.…”

Section: Discussionmentioning

confidence: 99%

Cells test substrate rigidity by local contractions on submicrometer pillars

Ghassemi

Meacci

Liu

et al. 2012

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

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248

274

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Cell growth and differentiation are critically dependent upon matrix rigidity, yet many aspects of the cellular rigidity-sensing mechanism are not understood. Here, we analyze matrix forces after initial cell-matrix contact, when early rigidity-sensing events occur, using a series of elastomeric pillar arrays with dimensions extending to the submicron scale (2, 1, and 0.5 μm in diameter covering a range of stiffnesses). We observe that the cellular response is fundamentally different on micron-scale and submicron pillars. On 2-μm diameter pillars, adhesions form at the pillar periphery, forces are directed toward the center of the cell, and a constant maximum force is applied independent of stiffness. On 0.5-μm diameter pillars, adhesions form on the pillar tops, and local contractions between neighboring pillars are observed with a maximum displacement of ∼60 nm, independent of stiffness. Because mutants in rigidity sensing show no detectable displacement on 0.5-μm diameter pillars, there is a correlation between local contractions to 60 nm and rigidity sensing. Localization of myosin between submicron pillars demonstrates that submicron scale myosin filaments can cause these local contractions. Finally, submicron pillars can capture many details of cellular force generation that are missed on larger pillars and more closely mimic continuous surfaces.cell mechanics | mechanotransduction | nanofabrication T he rigidity of matrix substrates provides important signals that determine cell growth (1), differentiation (2, 3), adhesion (4), or motility (5), among others. How the cellular motility machinery can sense matrix rigidity is unknown, but the mechanism(s) of rigidity sensing must be constrained by the size of the rigidity sensing machinery and the physical quantity "measured" by the cell (6). Arrays of elastomeric micropillars have proven to be a valuable tool in measuring cellular forces: optical microscopy can be used to precisely measure pillar displacement and generate real-time force maps across entire cells (7, 8). For example, over the time scale of hours to days, fibroblasts on arrays of 1-and 2-μm diameter pillars generate average displacements on the order of 100 nm independent of the pillar stiffness over a range of 2-130 nN/μm, i.e., the cells respond to rigidity by measuring the force required to produce a constant displacement (9). However, no studies have examined forces during the initial contact between the cell and the substrate, when the first rigiditysensing events take place (10). Moreover, in studies of the minimal cell-substrate contact area needed to sense rigidity and assemble adhesions, fibroblasts assembled adhesion contacts at the edges of beads with contact areas of more than ∼1 μm 2 , whereas with submicron beads, adhesion contacts only assembled after force from a rigid laser tweezers was applied (11). Analysis of bead displacement with laser tweezers also suggests that cells measure the force required for local displacements of ∼100 nm to deduce rigidity, i.e., a constant displ...

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“…To elucidate the role of phospho-Tyr789 PTP␣, we determined whether other integrin signaling events that are defective in PTP␣ Ϫ/Ϫ MEFs could be rescued by adenovirusmediated expression of wild-type (WT) PTP␣ or an unphosphorylatable mutant (Y789F) form of PTP␣. The integrin-induced tyrosine phosphorylation of the scaffolding protein Cas, an important regulator of cell migration (7,21), is impaired in MEFs lacking PTP␣ due to the reduced activity of the PTP␣-regulated Src family kinases (Src and Fyn) that phosphorylate Cas (22,40). Expressing WT PTP␣ in PTP␣ Ϫ/Ϫ MEFs restored the defective Cas tyrosine phosphorylation when suspended cells were placed on dishes coated with the integrin ligand fibronectin (FN) (Fig.…”

Section: Ptp␣-tyr789 Is Necessary For Efficient Integrin-induced Cas mentioning

confidence: 99%

“…These events are impaired in PTP␣-null MEFs, including downstream signaling events such as tyrosine phosphorylation of the scaffolding/ adaptor proteins p130Cas (Cas) and paxillin, activation of the RhoGTPase Rac1, and activation of the Erk mitogen-activated protein kinases (8,19,40). In MEFs and hippocampal neurons, force transduction in the integrin-mediated matrix rigidity response requires PTP␣-dependent recruitment of Fyn and tyrosine phosphorylation of Cas at the leading edge to regulate early spreading of fibroblasts or neurite extension (22,23).…”

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confidence: 99%

Protein Tyrosine Phosphatase α Phosphotyrosyl-789 Binds BCAR3 To Position Cas for Activation at Integrin-Mediated Focal Adhesions

Sun

Cheng

Chen

et al. 2012

Molecular and Cellular Biology

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Integrin-mediated focal adhesions connect the extracellular matrix and cytoskeleton to regulate cell responses, such as migration. Protein tyrosine phosphatase ␣ (PTP␣) regulates integrin signaling, focal adhesion formation, and migration, but its roles in these events are incompletely understood. The integrin-proximal action of PTP␣ activates Src family kinases, and subsequent phosphorylation of PTP␣ at Tyr789 acts in an unknown manner to promote migration. PTP␣-null cells were used in reconstitution assays to distinguish PTP␣-Tyr789-dependent signaling events. This showed that PTP␣-Tyr789 regulates the localization of PTP␣ and the scaffolding protein Cas to adhesion sites where Cas interacts with and is phosphorylated by Src to initiate Cas signaling. Linking these events, we identify BCAR3 as a molecular connector of PTP␣ and Cas, with phospho-Tyr789 PTP␣ serving as the first defined cellular ligand for the BCAR3 SH2 domain that recruits BCAR3-Cas to adhesions. Our findings reveal a novel role of PTP␣ in integrin-induced adhesion assembly that enables Src-mediated activation of the pivotal function of Cas in migration.

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RPTPα is required for rigidity-dependent inhibition of extension and differentiation of hippocampal neurons

Cited by 97 publications

References 83 publications

Retention and Silencing of Prepro-GnRH-II and Type II GnRH Receptor Genes in Mammals

Retention and Silencing of Prepro-GnRH-II and Type II GnRH Receptor Genes in Mammals

Cells test substrate rigidity by local contractions on submicrometer pillars

Protein Tyrosine Phosphatase α Phosphotyrosyl-789 Binds BCAR3 To Position Cas for Activation at Integrin-Mediated Focal Adhesions

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