Nuclear Localization of the ERK MAP Kinase Mediated by<i>Drosophila</i>αPS2βPS Integrin and Importin-7

James, Brian P.; Bunch, Thomas A.; Krishnamoorthy, Srinivasan; Perkins, Lizabeth A.; Brower, Danny L.

doi:10.1091/mbc.e06-07-0659

Cited by 33 publications

(31 citation statements)

References 62 publications

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“…Confirming an earlier report, we found endogenous Msk concentrated around the nuclear rim, with some overlap with MAb414 staining (Fig. 7A) (15). The immunofluorescence staining was highly specific, since msk RNAi abolished the signals (data not shown).…”

Section: Vol 30 2010 Scaffold Nucleoporins Required For Smad Nucleasupporting

confidence: 92%

Specific Nucleoporin Requirement for Smad Nuclear Translocation

Chen

2010

Molecular and Cellular Biology

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Cytoplasm-to-nucleus translocation of Smad is a fundamental step in transforming growth factor ␤ (TGF-␤) signal transduction. Here we identify a subset of nucleoporins that, in conjunction with Msk (Drosophila Imp7/8), specifically mediate activation-induced nuclear translocation of MAD (Drosophila Smad1) but not the constitutive import of proteins harboring a classic nuclear localization signal (cNLS) or the spontaneous nuclear import of Medea (Drosophila Smad4). Surprisingly, many of these nucleoporins, including Sec13, Nup75, Nup93, and Nup205, are scaffold nucleoporins considered important for the overall integrity of the nuclear pore complex (NPC) but not known to have cargo-specific functions. We demonstrate that the roles of these nucleoporins in supporting Smad nuclear import are separate from their previously assigned functions in NPC assembly. Furthermore, we uncovered novel pathway-specific functions of Sec13 and Nup93; both Sec13 and Nup93 are able to preferentially interact with the phosphorylated/activated form of MAD, and Nup93 acts to recruit the importin Msk to the nuclear periphery. These findings, together with the observation that Sec13 and Nup93 could interact directly with Msk, suggest their direct involvement in the nuclear import of MAD. Thus, we have delineated the nucleoporin requirement of MAD nuclear import, reflecting a unique trans-NPC mechanism.Transforming growth factor ␤ (TGF-␤) cytokines critically regulate a diverse array of cellular properties in development and homeostasis, through an evolutionarily conserved mechanism that centers around the Smad transcription factors (18, 34). TGF-␤ induces phosphorylation of the Smad proteins and consequently drives Smads into the nucleus, ensuring that changes in the gene transcription program are strictly signal dependent (24,26). Two critical elements in nuclear import are the transport receptors (i.e., karyopherins or importins) and the nuclear pore complex (NPC) (28, 30). We recently identified Imp7/8 as the importin for TGF-␤-activated Smads, but how the Imp7/8-Smad complex translocates through the NPC has yet to be elucidated (36). The NPC consists of more than 30 evolutionarily conserved nucleoporins, each with a particular localization within the NPC based on biochemical, biophysical, electron microscopy, and computational studies (2,3,25). Many nucleoporins contain repeats of phenylalanine-glycine (FG), and the highly hydrophobic and unstructured FG domains occupy the central tunnel of the NPC, constituting a gating mechanism that restricts the movement of macromolecules through the NPC (19). In vivo genetic studies have suggested redundancy among FG domains in maintaining the permeability barrier as well as nuclear import (29, 38). On the other hand, many of the non-FG nucleoporins assemble into subcomplexes within the NPC, most prominently the Nup107-160 (consisting of Nup107, Nup133, Nup75, Sec13, and Seh1, etc.) and Nup53-93 (containing Nup53, Nup93, and Nup205, etc.) complexes, and they are believed to serve mostly as scaffo...

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Section: Vol 30 2010 Scaffold Nucleoporins Required For Smad Nucleasupporting

confidence: 92%

Specific Nucleoporin Requirement for Smad Nuclear Translocation

Chen

2010

Molecular and Cellular Biology

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“…Alleles of msk were identified in a screen for dominant suppressors of an activated integrin αPS2 wing phenotype called Blistermaker (Baker et al, 2002). Consistent with this, Msk protein is found at the cell cortex in S2 cells where it colocalizes with integrins in a Csw-dependent manner (James et al, 2007). Furthermore, the nuclear accumulation of MAPK is compromised if there is a reduction in Msk protein levels or decrease in integrin function.…”

Section: Introductionmentioning

confidence: 57%

“…Consistent with a role in the RTK signaling pathway, Msk can bind to and transport the doubly phosphorylated, activated form of D-ERK (dp-ERK, or MAP kinase, hereafter referred to as MAPK) into the nucleus (James et al, 2007; Lorenzen et al, 2001). Since activated MAPK can function in both the cytoplasm and nucleus to activate downstream targets, the nucleocytoplasmic distribution of activated MAPK is important for determining downstream phenotypic outputs of the RTK pathway.…”

Section: Introductionmentioning

confidence: 99%

Moleskin is essential for the formation of the myotendinous junction in Drosophila

Liu

Geisbrecht

2011

Developmental Biology

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It is the precise connectivity between skeletal muscles and their corresponding tendon cells to form a functional myotendinous junction (MTJ) that allows for the force generation required for muscle contraction and organismal movement. The Drosophila MTJ is comprised of secreted extracellular matrix (ECM) proteins deposited between integrin-mediated hemi-adherens junctions on the surface of muscle and tendon cells. In this paper, we have identified a novel, cytoplasmic role for the canonical nuclear import protein Moleskin (Msk) in Drosophila embryonic somatic muscle attachment. Msk protein is enriched at muscle attachment sites in late embryogenesis and msk mutant embryos exhibit a failure in muscle-tendon cell attachment. Although the muscle-tendon attachment sites are reduced in size, components of the integrin complexes and ECM proteins are properly localized in msk mutant embryos. However, msk mutants fail to localize phosphorylated Focal adhesion kinase (pFAK) to the sites of muscle-tendon cell junctions. In addition, the tendon cell specific proteins Stripe (Sr) and activated mitogen-activated protein kinase (MAPK) are reduced in msk mutant embryos. Our rescue experiments demonstrate that Msk is required in the muscle cell, but not in the tendon cells. Moreover, muscle attachment defects due to loss of Msk are rescued by an activated form of MAPK or the secreted Epidermal Growth Factor receptor (Egfr) ligand Vein. Taken together, these findings provide strong evidence that Msk signals non-autonomously through the Vein-Egfr signaling pathway for late tendon cell late differentiation and/or maintenance.

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“…These mutations may indicate that import of transcription factors and signaling proteins such as the MAP kinases (25), potentially required for transcription of cellulase genes, may be limiting at this stage.…”

Section: Discussionmentioning

confidence: 99%

Tracking the roots of cellulase hyperproduction by the fungus Trichoderma reesei using massively parallel DNA sequencing

Crom

Schackwitz

Pennacchio

et al. 2009

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

178

170

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Trichoderma reesei (teleomorph Hypocrea jecorina) is the main industrial source of cellulases and hemicellulases harnessed for the hydrolysis of biomass to simple sugars, which can then be converted to biofuels such as ethanol and other chemicals. The highly productive strains in use today were generated by classical mutagenesis. To learn how cellulase production was improved by these techniques, we performed massively parallel sequencing to identify mutations in the genomes of two hyperproducing strains (NG14, and its direct improved descendant, RUT C30). We detected a surprisingly high number of mutagenic events: 223 single nucleotides variants, 15 small deletions or insertions, and 18 larger deletions, leading to the loss of more than 100 kb of genomic DNA. From these events, we report previously undocumented non-synonymous mutations in 43 genes that are mainly involved in nuclear transport, mRNA stability, transcription, secretion/vacuolar targeting, and metabolism. This homogeneity of functional categories suggests that multiple changes are necessary to improve cellulase production and not simply a few clear-cut mutagenic events. Phenotype microarrays show that some of these mutations result in strong changes in the carbon assimilation pattern of the two mutants with respect to the wild-type strain QM6a. Our analysis provides genome-wide insights into the changes induced by classical mutagenesis in a filamentous fungus and suggests areas for the generation of enhanced T. reesei strains for industrial applications such as biofuel production. biofuels ͉ biotechnology

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Nuclear Localization of the ERK MAP Kinase Mediated byDrosophilaαPS2βPS Integrin and Importin-7

Cited by 33 publications

References 62 publications

Specific Nucleoporin Requirement for Smad Nuclear Translocation

Specific Nucleoporin Requirement for Smad Nuclear Translocation

Moleskin is essential for the formation of the myotendinous junction in Drosophila

Tracking the roots of cellulase hyperproduction by the fungus Trichoderma reesei using massively parallel DNA sequencing

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