The N-terminal 209-aa domain of high molecular- weight 4.1R isoforms abrogates 4.1R targeting to the nucleus

Luque, Carlos M.; Lallena, Marı́a-José; Pérez-Ferreiro, Carmen M.; Isidro, Yolanda de; Cárcer, Guillermo de; Alonso, Miguel A.; Correas, Isabel

doi:10.1073/pnas.96.26.14925

Cited by 18 publications

(27 citation statements)

References 35 publications

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“…A third signal comprising basic amino acids coded by the alternative exon 16 have also been involved in 4.1R nuclear targeting (33,36). Finally, a fourth region mediating 4.1R intracellular localization is the 209-amino acid head piece (HP) of high molecular weight 4.1R 135 isoforms that inhibits nuclear targeting of 4.1R (37). The complexity of signals and regions identified to date as being involved in 4.1R nuclear and cytoplasmic distribution and the hierarchical fashion in which they regulate the intracellular localization of 4.1R are summarized in Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, a fourth group of 4.1R 135 isoforms contains the HP domain that inhibits nuclear targeting of 4.1R (37). The HP domain might adopt a conformation masking the regions involved in 4.1R nuclear targeting.…”

Section: Discussionmentioning

confidence: 99%

“…In our previous studies, which focused on the identification of signals involved in differential intracellular localization of proteins 4.1R (33,34,37), we showed that a constitutive region of the 4.1R molecule, one that is therefore present in all 4.1R isoforms and is thus designated as the "core region," was re-sponsible for nuclear targeting of 4.1R (34). Because 4.1R isoforms expressing exon 5 are predominantly localized in the cytoplasm (34), in this study we have aimed to identify the amino acid sequence that is responsible for this effect.…”

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confidence: 99%

“…4.1R is known to interact with nuclear components of the splicing machinery (19,22), pICln (28), a regulator of a chloride channel recently shown also to associate with spliceosomal proteins (29), interphase microtubules (30), a novel centrosomal protein termed CPAP (31), and the nuclear mitotic apparatus protein (32). Transfection studies using 4.1R cDNAs isolated from different sources have allowed the identification of specific nuclear isoforms of 4.1R (32)(33)(34)(35) and the signals involved in 4.1R nuclear targeting (33,34,36) and the abrogation of its nuclear accumulation (34,37).…”

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confidence: 99%

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An Alternative Domain Containing a Leucine-rich Sequence Regulates Nuclear Cytoplasmic Localization of Protein 4.1R

Luque¹,

Pérez-Ferreiro²,

Pérez-González³

et al. 2003

Journal of Biological Chemistry

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In red blood cells, protein 4.1 (4.1R) is an 80-kDa protein that stabilizes the spectrin-actin network and anchors it to the plasma membrane. The picture is more complex in nucleated cells, in which many 4.1R isoforms, varying in size and intracellular location, have been identified. To contribute to the characterization of signals involved in differential intracellular localization of 4.1R, we have analyzed the role the exon 5-encoded sequence plays in 4.1R distribution. We show that exon 5 encodes a leucine-rich sequence that shares key features with nuclear export signals (NESs). This sequence adopts the topology employed for NESs of other proteins and conserves two hydrophobic residues that are shown to be critical for NES function. A 4.1R isoform expressing the leucine-rich sequence binds to the export receptor CRM1 in a RanGTP-dependent fashion, whereas this does not occur in a mutant whose two conserved hydrophobic residues are substituted. These two residues are also essential for 4.1R intracellular distribution, because the 4.1R protein containing the leucine-rich sequence localizes in the cytoplasm, whereas the mutant protein predominantly accumulates in the nucleus. We hypothesize that the leucine-rich sequence in 4.1R controls distribution and concomitantly function of a specific set of 4.1R isoforms.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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An Alternative Domain Containing a Leucine-rich Sequence Regulates Nuclear Cytoplasmic Localization of Protein 4.1R

Luque¹,

Pérez-Ferreiro²,

Pérez-González³

et al. 2003

Journal of Biological Chemistry

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“…Although the expression pattern of 4.1R in mature mammalian red cells is relatively simple, multiple isoforms of 4.1R with variable N-terminal extensions and internal sequences are expressed in nonerythroid cells, mainly as a result of extensive alternative splicing of the 4.1R-encoding pre-mRNA (Conboy, 1999;Tang et al, 1990). The localization of protein 4.1R in nonerythroid cells is not restricted to the subjacent area beneath the plasma membrane, as 4.1R has also been identified at the nucleoskeleton (De Carcer et al, 1995), the centrosome Perez-Ferreiro et al, 2004), the endoplasmic reticulum (Luque et al, 1999) and microtubules (Perez-Ferreiro et al, 2001), thereby showing that 4.1R functions at multiple sites in the cell. The interaction of protein 4.1R with zonula occludens (ZO)-2 (Mattagajasingh et al, 2000) and with -catenin and E-cadherin (Yang et al, 2009) suggested that 4.1R might act as a linker between tight and adherens junctions and the actin cytoskeleton.…”

Section: Introductionmentioning

confidence: 99%

Protein 4.1R regulates cell migration and IQGAP1 recruitment to the leading edge

Ruiz-Sáenz

Kremer

Alonso

et al. 2011

Journal of Cell Science

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In red blood cells, multifunctional protein 4.1R stabilizes the spectrin–actin network and anchors it to the plasma membrane. To contribute to the characterization of functional roles of 4.1R in nonerythroid cells, we have analyzed the participation of protein 4.1R in cell migration. The distribution of endogenous 4.1R is polarized towards the leading edge of migrating cells. Exogenous 4.1R isoforms containing a complete membrane-binding domain consistently localized to plasma membrane extensions enriched in F-actin. Silencing of 4.1R caused the loss of persistence of migration in subconfluent cells and of directional migration in cells moving into a wound. Coimmunoprecipitation and pull-down assays identified the scaffold protein IQGAP1 as a partner for protein 4.1R and showed that the 4.1R membrane-binding domain is involved in binding IQGAP1. Importantly, we show that protein 4.1R is necessary for the localization of IQGAP1 to the leading edge of cells migrating into a wound, whereas IQGAP1 is not required for protein 4.1R localization. Collectively, our results indicate a crucial role for protein 4.1R in cell migration and in the recruitment of the scaffold protein IQGAP1 to the cell front.

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The spectrin–ankyrin–4.1–adducin membrane skeleton: adapting eukaryotic cells to the demands of animal life

2010

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The cells in animals face unique demands beyond those encountered by their unicellular eukaryotic ancestors. For example, the forces engendered by the movement of animals places stresses on membranes of a different nature than those confronting free-living cells. The integration of cells into tissues, as well as the integration of tissue function into whole animal physiology, requires specialisation of membrane domains and the formation of signalling complexes. With the evolution of mammals, the specialisation of cell types has been taken to an extreme with the advent of the non-nucleated mammalian red blood cell. These and other adaptations to animal life seem to require four proteins--spectrin, ankyrin, 4.1 and adducin--which emerged during eumetazoan evolution. Spectrin, an actin cross-linking protein, was probably the earliest of these, with ankyrin, adducin and 4.1 only appearing as tissues evolved. The interaction of spectrin with ankyrin is probably a prerequisite for the formation of tissues; only with the advent of vertebrates did 4.1 acquires the ability to bind spectrin and actin. The latter activity seems to allow the spectrin complex to regulate the cell surface accumulation of a wide variety of proteins. Functionally, the spectrin-ankyrin-4.1-adducin complex is implicated in the formation of apical and basolateral domains, in aspects of membrane trafficking, in assembly of certain signalling and cell adhesion complexes and in providing stability to otherwise mechanically fragile cell membranes. Defects in this complex are manifest in a variety of hereditary diseases, including deafness, cardiac arrhythmia, spinocerebellar ataxia, as well as hereditary haemolytic anaemias. Some of these proteins also function as tumor suppressors. The spectrin-ankyrin-4.1-adducin complex represents a remarkable system that underpins animal life; it has been adapted to many different functions at different times during animal evolution.

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The N-terminal 209-aa domain of high molecular- weight 4.1R isoforms abrogates 4.1R targeting to the nucleus

Cited by 18 publications

References 35 publications

An Alternative Domain Containing a Leucine-rich Sequence Regulates Nuclear Cytoplasmic Localization of Protein 4.1R

An Alternative Domain Containing a Leucine-rich Sequence Regulates Nuclear Cytoplasmic Localization of Protein 4.1R

Protein 4.1R regulates cell migration and IQGAP1 recruitment to the leading edge

The spectrin–ankyrin–4.1–adducin membrane skeleton: adapting eukaryotic cells to the demands of animal life

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