The human intersectin genes and their spliced variants are differentially expressed

Pucharcós, Carles; Casas, Caty; Nadal, Marga; Estivill, Xavier; Luna, Susana de la

doi:10.1016/s0167-4781(01)00276-7

Cited by 62 publications

(81 citation statements)

References 47 publications

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“…We examined interactions between long WNK1 and SH3 domains of ITSN, endophilin, and amphiphysin. In humans, rats and mice, there are 2 ITSN genes, ITSN1 and ITSN2 (22)(23)(24). Each ITSN gene gives rise to alternatively spliced long and short forms.…”

Section: Long Wnk1 Decreases Surface Abundance Of Romk1 Via a Dynaminmentioning

confidence: 99%

“…The short form of ITSN1 (ITSN1s) is ubiquitous (23,24) and contains 2 Eps15 homology (EH) domains, a central coiled-coil region, and 5 consecutive SH3 domains (SH3A-SH3E; Figure 2A). The long form additionally contains Dbl homology, pleckstrin homology, and C2 domains in the C terminus (22)(23)(24). Amino acids 1-491 of long WNK1 are sufficient for regulation of ROMK1 (13).…”

Section: Long Wnk1 Decreases Surface Abundance Of Romk1 Via a Dynaminmentioning

confidence: 99%

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Intersectin links WNK kinases to endocytosis of ROMK1

He¹,

Wang²,

Huang³

et al. 2007

J. Clin. Invest.

137

180

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Section: Long Wnk1 Decreases Surface Abundance Of Romk1 Via a Dynaminmentioning

confidence: 99%

Section: Long Wnk1 Decreases Surface Abundance Of Romk1 Via a Dynaminmentioning

confidence: 99%

Intersectin links WNK kinases to endocytosis of ROMK1

He¹,

Wang²,

Huang³

et al. 2007

J. Clin. Invest.

137

180

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“…In mammals, two intersectin genes, ITSN-1 and ITSN-2, code for several alternatively spliced isoforms (Pucharcos et al, 2001). The two major isoforms, for both intersectins, are 1) the ubiquitous ITSN-short, containing two EH domains, a coiled-coil region, and five Src homology (SH)3 domains; and 2) the neuronal specific (or quasi-specific) ITSN-long, displaying a C-terminal extension, consisting of a Dbl homology-pleckstrin homology (DH-PH) domain, followed by a C2 domain .…”

Section: Introductionmentioning

confidence: 99%

Caenorhabditis elegansIntersectin: A Synaptic Protein Regulating Neurotransmission

Rose¹,

Malabarba

Krag³

et al. 2007

MBoC

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Intersectin is a multifunctional protein that interacts with components of the endocytic and exocytic pathways, and it is also involved in the control of actin dynamics. Drosophila intersectin is required for viability, synaptic development, and synaptic vesicle recycling. Here, we report the characterization of intersectin function in Caenorhabditis elegans. Nematode intersectin (ITSN-1) is expressed in the nervous system, and it is enriched in presynaptic regions. The C. elegans intersectin gene (itsn-1) is nonessential for viability. In addition, itsn-1-null worms do not display any evident phenotype, under physiological conditions. However, they display aldicarb-hypersensitivity, compatible with a negative regulatory role of ITSN-1 on neurotransmission. ITSN-1 physically interacts with dynamin and EHS-1, two proteins involved in synaptic vesicle recycling. We have previously shown that EHS-1 is a positive modulator of synaptic vesicle recycling in the nematode, likely through modulation of dynamin or dynamin-controlled pathways. Here, we show that ITSN-1 and EHS-1 have opposite effects on aldicarb sensitivity, and on dynamin-dependent phenotypes. Thus, the sum of our results identifies dynamin, or a dynamin-controlled pathway, as a potential target for the negative regulatory role of ITSN-1.

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“…This GEF is unusual in that the DH and PH domains are not fundamental to the cellular role of the protein and are instead alternatively spliced onto a ubiquitously expressed isoform, intersectin 1S (Guipponi et al, 1998;Hussain et al, 1999;Pucharcos et al, 2001). Intersectin 1S, which binds multiple endocytic proteins, is localized to sites of clathrin-mediated endocytosis through protein interactions with its EH domains Sengar et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Intersectin 1L Guanine Nucleotide Exchange Activity Is Regulated by Adjacent src Homology 3 Domains That Are Also Involved in Endocytosis

Zamanian

Kelly

2003

MBoC

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Intersectin 1L is a scaffolding protein involved in endocytosis that also has guanine nucleotide exchange activity for Cdc42. In the context of the full-length protein, the catalytic exchange activity of the DH domain is repressed. Here we use biochemical methods to dissect the mechanism for this inhibition. We demonstrate that the intersectin 1L SH3 domains, which bind endocytic proteins, directly inhibit the activity of the DH domain in assays for both binding and exchange of Cdc42. This inhibitory mechanism seems to act through steric hindrance of Cdc42 binding by an intramolecular interaction between the intersectin 1L SH3 domain region and the adjacent DH domain. Surprisingly, the mode of SH3 domain binding is other than through the proline peptide binding pocket. The dual role of the SH3 domains in endocytosis and repression of exchange activity suggests that the intersectin 1L exchange activity is regulated by endocytosis. We show that the endocytic protein, dynamin, competes for binding to the SH3 domains with the neural Wiskott-Aldrich Syndrome protein, an actin filament nucleation protein that is a substrate for activated Cdc42. Swapping of SH3 domain binding partners might act as a switch controlling the actin nucleation activity of intersectin 1L. INTRODUCTIONRho family guanine nucleotide exchange factors (GEFs) are critical regulatory proteins of cellular pathways that require regulation of actin cytoskeleton rearrangements (for review see Zheng, 2001;Hoffman and Cerione, 2002). Their conserved catalytic domain, the Dbl homology (DH) domain (Hart et al., 1991(Hart et al., , 1994 catalyzes the release of GDP from Rho GTPases and thus subsequent activation by GTP binding. DH domains are invariably found upstream and adjacent to pleckstrin homology (PH) domains, which are thought to influence their activity (Liu et al., 1998;Das et al., 2000) and membrane localization (Whitehead et al., 1999). The noncatalytic parts of the structurally complex GEFs link the exchange activity to cellular processes and inhibit the DH domain exchange activity (Zheng, 2001;Hoffman and Cerione, 2002). Cellular inputs, such as protein (Hart et al., 1998;Scita et al., 1999;Innocenti et al., 2002) and phospholipid binding to (Han et al., 1998;Nimnual et al., 1998;Crompton et al., 2000;Das et al., 2000;Russo et al., 2001), and phosphorylation of (Crespo et al., 1997;Han et al., 1997;Schuebel et al., 1998;Aghazadeh et al., 2000) these regulatory regions derepress exchange activity. Integration of cellular signals by Rho GEFs can focus GTPase activity to allow temporal and spatially localized activation of actin cytoskeletal rearrangements.Intersectin 1L, a neuronal splice variant of the endocytic scaffolding protein intersectin 1, is a Rho family GEF that is composed of two N-terminal EH domains (EH1, EH2), a large region of putative coiled-coils, five SH3 domains (SH3A, B, C, D, and E; Roos and Kelly, 1998;Yamabhai et al., 1998;Okamoto et al., 1999;Sengar et al., 1999), followed by the DH and PH domains and a carboxyl-terminal ...

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The human intersectin genes and their spliced variants are differentially expressed

Cited by 62 publications

References 47 publications

Intersectin links WNK kinases to endocytosis of ROMK1

Intersectin links WNK kinases to endocytosis of ROMK1

Caenorhabditis elegansIntersectin: A Synaptic Protein Regulating Neurotransmission

Intersectin 1L Guanine Nucleotide Exchange Activity Is Regulated by Adjacent src Homology 3 Domains That Are Also Involved in Endocytosis

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