Microexon-based regulation of ITSN1 and Src SH3 domains specificity relies on introduction of charged amino acids into the interaction interface

Dergai, Mykola; Tsyba, Lyudmila; Dergai, Oleksandr; Zlatskii, I. A.; Skrypkina, Inessa; Коваленко, В. В.; Rynditch, A. V.

doi:10.1016/j.bbrc.2010.07.080

Cited by 20 publications

(19 citation statements)

References 30 publications

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“…Src (Black, 1991), Bin1, Agrn, Dock9, Shank2, Robo1 ) associated with axonogenesis and the formation and function of synapses. Supporting such functions, an alternative microexon overlapping the SH3A domain of Intersectin 1 (Itsn1) has been reported to promote an interaction with Dynamin 1, and was proposed to modulate roles of Itsn1 in endocytosis, cell signaling and/or actin-cytoskeleton dynamics (Dergai et al, 2010). A neural-specific microexon in Protrudin/Zfyve27 was recently shown to increase its interaction with the vesicle-associated membrane protein-associated protein (VAP), and to promote neurite outgrowth (Ohnishi et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

A Highly Conserved Program of Neuronal Microexons Is Misregulated in Autistic Brains

Irimia

Weatheritt

Ellis

et al. 2014

Cell

572

841

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Summary Alternative splicing (AS) generates vast transcriptomic and proteomic complexity. However, which of the myriad of detected AS events provide important biological functions is not well understood. Here, we define the largest program of functionally coordinated, neural-regulated AS described to date in mammals. Relative to all other types of AS within this program, 3-15 nucleotide ‘microexons’ display the most striking evolutionary conservation and switch-like regulation. These microexons modulate the function of interaction domains of proteins involved in neurogenesis. Most neural microexons are regulated by the neuronal-specific splicing factor nSR100/SRRM4, through its binding to adjacent intronic enhancer motifs. Neural microexons are frequently misregulated in the brains of individuals with autism spectrum disorder, and this misregulation is associated with reduced levels of nSR100. The results thus reveal a highly conserved program of dynamic microexon regulation associated with the remodeling of protein interaction networks during neurogenesis, the misregulation of which is linked to autism.

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Section: Discussionmentioning

confidence: 99%

A Highly Conserved Program of Neuronal Microexons Is Misregulated in Autistic Brains

Irimia

Weatheritt

Ellis

et al. 2014

Cell

572

841

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“…Previously we described two splicing events affecting exons 6 and 20 of the ITSN1 pre-mRNA: i) inclusion of exon 6′ instead of 6 results in deletion of 37 amino acids between the EH1 and EH2 domains (Tsyba et al, 2004); ii) neuron-specific inclusion of exon 20 that leads to a modification in the structure and ligand specificity of the SH3A domain (Dergai et al, 2010;Tsyba et al, 2008).…”

Section: Itsn1 Isoform With Alternative 3′-end Is Specific Of Placentmentioning

confidence: 99%

“…All PCR-generated DNA fragments were sequenced to confirm fidelity. The constructs expressing the GST fused SH3A domain of ITSN1 and the SH3 domain of amhiphysin 1 were described previously (Dergai et al, 2010;Tsyba et al, 2008).…”

Section: Expression Constructsmentioning

confidence: 99%

Identification and characterization of a novel mammalian isoform of the endocytic adaptor ITSN1

Dergai

Skrypkina

Dergai

et al. 2011

Gene

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“…One study examined the biochemical consequences of splicing a neuron-specific exon (microexon 20) within the SH3A domain of ITSN1, resulting in the inclusion of 5 additional amino acids in the n-Src loop of SH3A [24]. These additional amino acids reduced binding to SOS and Cbl, compared to ITSN1-S. Dergai and colleagues showed that microexon 20 in the SH3A domain of ITSN1 regulates interaction with dynamin 1 [25]. The authors examined the genomic sequences of ITSN1 from human, mouse, rat, chicken, and zebrafish, and found that microexon 20 was conserved.…”

Section: The Itsn Gene Familymentioning

confidence: 99%

Emerging Roles for Intersectin (ITSN) in Regulating Signaling and Disease Pathways

Hunter

Russo

O’Bryan

2013

IJMS

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Intersectins (ITSNs) represent a family of multi-domain adaptor proteins that regulate endocytosis and cell signaling. ITSN genes are highly conserved and present in all metazoan genomes examined thus far. Lower eukaryotes have only one ITSN gene, whereas higher eukaryotes have two ITSN genes. ITSN was first identified as an endocytic scaffold protein, and numerous studies reveal a conserved role for ITSN in endocytosis. Subsequently, ITSNs were found to regulate multiple signaling pathways including receptor tyrosine kinases (RTKs), GTPases, and phosphatidylinositol 3-kinase Class 2beta (PI3KC2β). ITSN has also been implicated in diseases such as Down Syndrome (DS), Alzheimer Disease (AD), and other neurodegenerative disorders. This review summarizes the evolutionary conservation of ITSN, the latest research on the role of ITSN in endocytosis, the emerging roles of ITSN in regulating cell signaling pathways, and the involvement of ITSN in human diseases such as DS, AD, and cancer.

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Microexon-based regulation of ITSN1 and Src SH3 domains specificity relies on introduction of charged amino acids into the interaction interface

Cited by 20 publications

References 30 publications

A Highly Conserved Program of Neuronal Microexons Is Misregulated in Autistic Brains

A Highly Conserved Program of Neuronal Microexons Is Misregulated in Autistic Brains

Identification and characterization of a novel mammalian isoform of the endocytic adaptor ITSN1

Emerging Roles for Intersectin (ITSN) in Regulating Signaling and Disease Pathways

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