Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0282612 (PIN)
 2,291 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rac proteins of the Rho-like GTPase family, including the ubiquitous Rac1, the hematopoiesis-specific Rac2, and the least-characterized Rac3 play a major role in oncogenic transformation, tumor invasion and metastasis. However, the prognostic relevance of Rac expression in human tumors has not been investigated yet. In the present study, Rac protein expression was analyzed in benign secretory epithelium, high-grade prostatic intraepithelium neoplasia (HG-PIN), and prostate carcinomas of 60 R0-resected radical prostatectomy specimens by semiquantitative immunohistochemistry. Thus, Rac proteins were significantly strongly expressed in HG-PIN (P < 0.001) and prostate carcinomas (P < 0.001) when compared with benign secretory epithelium. Accordingly, all tumor tissues analyzed by isoform-specific real-time PCR (n = 7) exhibited significantly higher RNA expression levels of Rac (i.e. sum of Rac1 and Rac3 expression levels) than the respective benign counterparts (P = 0.018) and this appeared to result mainly from increased expression of the Rac3 isoform as verified by immunoblotting. Univariate analyses showed statistically significant associations of increased Rac protein expression in prostate cancer (P = 0.045), preoperative prostate-specific antigen levels (P = 0.044), pT stage (P = 0.002), and Gleason score (P = 0.001) with decreased disease-free survival (DFS). This prognostic effect of increased protein expression of Rac remained significant even in a multivariate analysis including all these four factors (relative risk = 3.22, 95% confidence interval = 1.04-10.00; P = 0.043). In conclusion, our data suggest that increased Rac protein expression in prostate cancer relative to the corresponding benign secretory epithelium is an independent predictor of decreased DFS and appears to result mainly from increased expression of the Rac3 isoform.
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PMID:Prognostic relevance of increased Rac GTPase expression in prostate carcinomas. 1763 41

Dynamically polarized membrane proteins define different cell boundaries and have an important role in intercellular communication-a vital feature of multicellular development. Efflux carriers for the signalling molecule auxin from the PIN family are landmarks of cell polarity in plants and have a crucial involvement in auxin distribution-dependent development including embryo patterning, organogenesis and tropisms. Polar PIN localization determines the direction of intercellular auxin flow, yet the mechanisms generating PIN polarity remain unclear. Here we identify an endocytosis-dependent mechanism of PIN polarity generation and analyse its developmental implications. Real-time PIN tracking showed that after synthesis, PINs are initially delivered to the plasma membrane in a non-polar manner and their polarity is established by subsequent endocytic recycling. Interference with PIN endocytosis either by auxin or by manipulation of the Arabidopsis Rab5 GTPase pathway prevents PIN polarization. Failure of PIN polarization transiently alters asymmetric auxin distribution during embryogenesis and increases the local auxin response in apical embryo regions. This results in ectopic expression of auxin pathway-associated root-forming master regulators in embryonic leaves and promotes homeotic transformation of leaves to roots. Our results indicate a two-step mechanism for the generation of PIN polar localization and the essential role of endocytosis in this process. It also highlights the link between endocytosis-dependent polarity of individual cells and auxin distribution-dependent cell fate establishment for multicellular patterning.
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PMID:Generation of cell polarity in plants links endocytosis, auxin distribution and cell fate decisions. 2503 Jan 76

In plants, polar transport of the hormone auxin between cells connects cell polarity and pattern formation and is thus required for plant development. The direction of auxin transport is determined by polar localization of PIN auxin efflux transporters. The dynamic polar localization of PIN proteins depends on constitutive endocytic recycling to and from the plasma membrane. However, it was not well understood how PIN polarization is connected to regulators of cell polarity. In a paper that was published in the January issue of PLoS Biology, 2010 we described the involvement of the ROP GTPase associated scaffold Interactor of Constitutive active ROP 1 (ICR1) in recruitment of PIN proteins to polar domains in the plasma membrane. icr1 mutant plants and embryos have severe developmental aberrations that are caused by abnormal auxin distribution. ICR1 functions at or close to the plasma membrane where it is required for exocytosis. ICR1 transcription is quickly induced by auxin but is post-transcriptionally repressed at the site of stable auxin maximum in embryos and roots. Thus, ICR1 integrates auxin-regulated transcription with ROP modulated cell polarity.
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PMID:An auxin regulated positive feedback loop integrates Rho modulated cell polarity with pattern formation. 2009 22

Understanding of eukaryotic ribosome synthesis has been slowed by a lack of structural data for the pre-ribosomal particles. We report rRNA-binding sites for six late-acting 40S ribosome synthesis factors, three of which cluster around the 3' end of the 18S rRNA in model 3D structures. Enp1 and Ltv1 were previously implicated in 'beak' structure formation during 40S maturation--and their binding sites indicate direct functions. The kinase Rio2, putative GTPase Tsr1 and dimethylase Dim1 bind sequences involved in tRNA interactions and mRNA decoding, indicating that their presence is incompatible with translation. The Dim1- and Tsr1-binding sites overlap with those of homologous Escherichia coli proteins, revealing conservation in assembly pathways. The primary binding sites for the 18S 3'-endonuclease Nob1 are distinct from its cleavage site and were unaltered by mutation of the catalytic PIN domain. Structure probing indicated that at steady state the cleavage site is likely unbound by Nob1 and flexible in the pre-rRNA. Nob1 binds before pre-rRNA cleavage, and we conclude that structural reorganization is needed to bring together the catalytic PIN domain and its target.
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PMID:Cracking pre-40S ribosomal subunit structure by systematic analyses of RNA-protein cross-linking. 2045 30

Endocytosis is crucial for various cellular functions and development of multicellular organisms. In mammals and yeast, ADP-ribosylation factor (ARF) GTPases, key components of vesicle formation, and their regulators ARF-guanine nucleotide exchange factors (GEFs) and ARF-GTPase-activating protein (GAPs) mediate endocytosis. A similar role has not been established in plants, mainly because of the lack of the canonical ARF and ARF-GEF components that are involved in endocytosis in other eukaryotes. In this study, we revealed a regulatory mechanism of endocytosis in plants based on ARF GTPase activity. We identified that ARF-GEF GNOM and ARF-GAP vascular network defective 3 (VAN3), both of which are involved in polar auxin transport-dependent morphogenesis, localize at the plasma membranes as well as in intracellular structures. Variable angle epifluorescence microscopy revealed that GNOM and VAN3 localize to partially overlapping discrete foci at the plasma membranes that are regularly associated with the endocytic vesicle coat clathrin. Genetic studies revealed that GNOM and VAN3 activities are required for endocytosis and internalization of plasma membrane proteins, including PIN-FORMED auxin transporters. These findings identified ARF GTPase-based regulatory mechanisms for endocytosis in plants. GNOM and VAN3 previously were proposed to function solely at the recycling endosomes and trans-Golgi networks, respectively. Therefore our findings uncovered an additional cellular function of these prominent developmental regulators.
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PMID:ADP-ribosylation factor machinery mediates endocytosis in plant cells. 2111 84

Phototropism is an adaptation response, through which plants grow towards the light. It involves light perception and asymmetric distribution of the plant hormone auxin. Here we identify a crucial part of the mechanism for phototropism, revealing how light perception initiates auxin redistribution that leads to directional growth. We show that light polarizes the cellular localization of the auxin efflux carrier PIN3 in hypocotyl endodermis cells, resulting in changes in auxin distribution and differential growth. In the dark, high expression and activity of the PINOID (PID) kinase correlates with apolar targeting of PIN3 to all cell sides. Following illumination, light represses PINOID transcription and PIN3 is polarized specifically to the inner cell sides by GNOM ARF GTPase GEF (guanine nucleotide exchange factor)-dependent trafficking. Thus, differential trafficking at the shaded and illuminated hypocotyl side aligns PIN3 polarity with the light direction, and presumably redirects auxin flow towards the shaded side, where auxin promotes growth, causing hypocotyls to bend towards the light. Our results imply that PID phosphorylation-dependent recruitment of PIN proteins into distinct trafficking pathways is a mechanism to polarize auxin fluxes in response to different environmental and endogenous cues.
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PMID:Light-mediated polarization of the PIN3 auxin transporter for the phototropic response in Arabidopsis. 2146 Aug 6

AUXIN BINDING PROTEIN 1 (ABP1) has long been proposed as an auxin receptor to regulate cell expansion. The embryo lethality of ABP1-null mutants demonstrates its fundamental role in plant development, but also hinders investigation of its involvement in post-embryonic processes and its mode of action. By taking advantage of weak alleles and inducible systems, several recent studies have revealed a role for ABP1 in organ development, cell polarization, and shape formation. In addition to its role in the regulation of auxin-induced gene expression, ABP1 has now been shown to modulate non-transcriptional auxin responses. ABP1 is required for activating two antagonizing ROP GTPase signaling pathways involved in cytoskeletal reorganization and cell shape formation, and participates in the regulation of clathrin-mediated endocytosis to subsequently affect PIN protein distribution. These exciting discoveries provide indisputable evidence for the auxin-induced signaling pathways that are downstream of ABP1 function, and suggest intriguing mechanisms for ABP1-mediated polar cell expansion and spatial coordination in response to auxin.
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PMID:Is ABP1 an auxin receptor yet? 2171 49

The investigation of Rho-family GTPases has uncovered mechanisms for spatiotemporal control of cellular processes such as cell polarization, movement, morphogenesis and cell division. Now Rho GTPase plays another leading role in the discovery of a new signaling mechanism for auxin, a multifunctional hormone that regulates pattern formation in plants. Arabidopsis leaf epidermal pavement cells (PCs) develop the puzzle-piece cell shape with interlocking lobes and indentations via interdigitated cellular growth.1 Through the ABP1 (Auxin Binding Protein 1) cell surface receptor, auxin coordinately activates 2 mutually exclusive Rho GTPase signaling pathways that are activated in the complementary lobing and indenting sides of adjacent cells: the ROP2 pathway for lobe formation and the ROP6 pathway for promoting indentation. This new signaling mechanism also involves ROP2-dependent polar accumulation of PIN1 in the plasma membrane, a member of the PIN auxin efflux carrier family that is critical for the formation of various developmental patterns including the PC interdigitation pattern. This Rho-dependent auxin signaling mechanism explains how interdigitated cellular growth is coordinated. In this extra view, we propose that the same mechanism can also explain how a uniform auxin signal initiates the formation of the interdigitated pattern.
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PMID:Uniform auxin triggers the Rho GTPase-dependent formation of interdigitation patterns in pavement cells. 2214 96

The dynamic spatial and temporal distribution of the crucial plant signaling molecule auxin is achieved by feedback coordination of auxin signaling and intercellular auxin transport pathways. Developmental roles of auxin have been attributed predominantly to its effect on transcription; however, an alternative pathway involving AUXIN BINDING PROTEIN1 (ABP1) has been proposed to regulate clathrin-mediated endocytosis in roots and Rho-like GTPase (ROP)-dependent pavement cell interdigitation in leaves. In this study, we show that ROP6 and its downstream effector RIC1 regulate clathrin association with the plasma membrane for clathrin-mediated endocytosis, as well as for its feedback regulation by auxin. Genetic analysis revealed that ROP6/RIC1 acts downstream of ABP1 to regulate endocytosis. This signaling circuit is also involved in the feedback regulation of PIN-FORMED 1 (PIN1) and PIN2 auxin transporters activity (via its constitutive endocytosis) and corresponding auxin transport-mediated processes, including root gravitropism and leave vascular tissue patterning. Our findings suggest that the signaling module auxin-ABP1-ROP6/RIC1-clathrin-PIN1/PIN2 is a shared component of the feedback regulation of auxin transport during both root and aerial development.
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PMID:ABP1 and ROP6 GTPase signaling regulate clathrin-mediated endocytosis in Arabidopsis roots. 2283 94

In the final steps of yeast ribosome synthesis, immature translation-incompetent pre-40S particles that contain 20S pre-rRNA are converted to the mature translation-competent subunits containing the 18S rRNA. An assay for 20S pre-rRNA cleavage in purified pre-40S particles showed that cleavage by the PIN domain endonuclease Nob1 was strongly stimulated by the GTPase activity of Fun12, the yeast homolog of cytoplasmic translation initiation factor eIF5b. Cleavage of the 20S pre-rRNA was also inhibited in vivo and in vitro by blocking binding of Fun12 to the 25S rRNA through specific methylation of its binding site. Cleavage competent pre-40S particles stably associated with Fun12 and formed 80S complexes with 60S ribosomal subunits. We propose that recruitment of 60S subunits promotes GTP hydrolysis by Fun12, leading to structural rearrangements within the pre-40S particle that bring Nob1 and the pre-rRNA cleavage site together.
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PMID:Proofreading of pre-40S ribosome maturation by a translation initiation factor and 60S subunits. 2295 31


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