The Role of Nonerythroid Spectrin<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M1"><mml:mrow><mml:mi>α</mml:mi></mml:mrow></mml:math>II in Cancer

Ackermann, Anne; Brieger, Angela

doi:10.1155/2019/7079604

Cited by 37 publications

(36 citation statements)

References 115 publications

(184 reference statements)

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“…The subsequent association of either Sptbn1 (275 kDa), or Itpr1 (310 kDa) would shift the mass to around 800 kDa. Sptan1 has a variety of binding domains where interactions with Kcc2 could occur, such as SH3 domains (Ackermann and Brieger, 2019). It has previously been proposed that Kcc2 also contains a non-canonical SH3 domain in its C-terminus (Llano et al, 2015).…”

Section: Kcc2 Is Associated With the Spectrin Cytoskeletonmentioning

confidence: 99%

Isolation and Characterization of Multi-Protein Complexes Enriched in the K-Cl Co-transporter 2 From Brain Plasma Membranes

Smalley

Kontou

Choi

et al. 2020

Front. Mol. Neurosci.

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Kcc2 plays a critical role in determining the efficacy of synaptic inhibition, however, the cellular mechanisms neurons use to regulate its membrane trafficking, stability and activity are ill-defined. To address these issues, we used affinity purification to isolate stable multi-protein complexes of K-Cl Co-transporter 2 (Kcc2) from the plasma membrane of murine forebrain. We resolved these using blue-native polyacrylamide gel electrophoresis (BN-PAGE) coupled to LC-MS/MS and label-free quantification. Data are available via ProteomeXchange with identifier PXD021368. Purified Kcc2 migrated as distinct molecular species of 300, 600, and 800 kDa following BN-PAGE. In excess of 90% coverage of the soluble N-and C-termini of Kcc2 was obtained. In total we identified 246 proteins significantly associated with Kcc2. The 300 kDa species largely contained Kcc2, which is consistent with a dimeric quaternary structure for this transporter. The 600 and 800 kDa species represented stable multi-protein complexes of Kcc2. We identified a set of novel structural, ion transporting, immune related and signaling protein interactors, that are present at both excitatory and inhibitory synapses, consistent with the proposed localization of Kcc2. These included spectrins, C1qa/b/c and the IP3 receptor. We also identified interactors more directly associated with phosphorylation; Akap5, Akap13, and Lmtk3. Finally, we used LC-MS/MS on the same purified endogenous plasma membrane Kcc2 to detect phosphorylation sites. We detected 11 sites with high confidence, including known and novel sites. Collectively our experiments demonstrate that Kcc2 is associated with components of the neuronal cytoskeleton and signaling molecules that may act to regulate transporter membrane trafficking, stability, and activity.

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Section: Kcc2 Is Associated With the Spectrin Cytoskeletonmentioning

confidence: 99%

Isolation and Characterization of Multi-Protein Complexes Enriched in the K-Cl Co-transporter 2 From Brain Plasma Membranes

Smalley

Kontou

Choi

et al. 2020

Front. Mol. Neurosci.

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“…bIVS5-spectrin is a predominantly nuclear isoform that associates with PML bodies 36 and the nuclear matrix 37 . aIIS*-spectrin is also found in association with the nuclear matrix (ibid) and has well-documented roles in DNA inter-strand crosslink repair mediated by the FANCA/C proteins in association with the XPF/XPG/XP complex 38,39 . bH has not yet been localized to the nuclear envelope or nucleoplasm by immunofluorescence; however, bH along with the other spectrins were identified as a component of the nuclear matrix 40 suggesting that the role of bH in cape formation and nuclear envelope biology could even be direct.…”

Section: Resultsmentioning

confidence: 99%

TheDrosophilaEGFR ligand mSpitz is delivered to cytoplasmic capes at sites of non-canonical RNA export on the nuclear envelopeviathe endosomal system

Mattie

Kumar²,

Travor

et al. 2020

Preprint

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Nuclear-cytoplasmic communication is not limited to nuclear pores, with both proteins and RNA using alternative routes between these compartments. We previously characterized cytoplasmic capes (large invaginations of the nuclear envelope in Drosophila), which are enriched for the membrane-bound EGF receptor ligand mSpitz, endosome-related organelles and ubiquitylated proteins. Closely associated with capes are groups of perinuclear vesicles resembling those seen at sites of RNP export via a budding mechanism. Here, we demonstrate that mSpitz delivery to capes requires passage through the endosomal system. We also show that capes are closely associated with sites of non-canonical RNP export as well as the dFrizzled2 receptor C terminal fragment, a core component of this export pathway. Video microscopy of glands in intact larvae indicates that cytoplasmic capes are stable structures that persist for at least 90 minutes without conspicuous growth. We further show that capes appear with the growth of the salivary gland rather than its developmental stage. Finally, we show that the large F-actin binding protein βH-spectrin, which modulates endosomal trafficking, as well as its partner βH-spectrin are required for cape formation. Cytoplasmic capes therefore represent a subspecialization of the nuclear envelope where endosomal trafficking and RNP export are closely associated.

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“…HL variants from Rotunno et al (2016) Variant in matched gene from present study involved in the catalysis of the second step in the biosynthesis of heme and also acts as an endogenous inhibitor of the 26 S proteasome, a multi-catalytic ATP-dependent protease complex that functions as the degrading arm of the ubiquitin system, which is the major pathway for regulated degradation of proteins in all eukaryotes. Down regulation of ALAD is shown to be associated with poor prognosis in patients with breast cancer (Ge et al, 2017) whereas the existing data on non-erythroid spectrin αII (SPTAN1) suggest that overexpression of SPTAN1 in tumor cells reflects neoplastic and tumor promoting activity or tumor suppressing effects by enabling DNA repair through interaction with DNA repair proteins (Ackermann and Brieger, 2019). CERCAM is known as an unfavorable prognostic marker in urothelial, renal, and ovarian cancers implying the importance of the variants in these genes (Ma et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Identification of Familial Hodgkin Lymphoma Predisposing Genes Using Whole Genome Sequencing

Srivastava

Galimberti

Kumar

et al. 2020

Front. Bioeng. Biotechnol.

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Hodgkin lymphoma (HL) is a lymphoproliferative malignancy of B-cell origin that accounts for 10% of all lymphomas. Despite evidence suggesting strong familial clustering of HL, there is no clear understanding of the contribution of genes predisposing to HL. In this study, whole genome sequencing (WGS) was performed on 7 affected and 9 unaffected family members from three HL-prone families and variants were prioritized using our Familial Cancer Variant Prioritization Pipeline (FCVPPv2). WGS identified a total of 98,564, 170,550, and 113,654 variants which were reduced by pedigree-based filtering to 18,158, 465, and 26,465 in families I, II, and III, respectively. In addition to variants affecting amino acid sequences, variants in promoters, enhancers, transcription factors binding sites, and microRNA seed sequences were identified from upstream, downstream, 5 ′ and 3 ′ untranslated regions. A panel of 565 cancer predisposing and other cancer-related genes and of 2,383 potential candidate HL genes were also screened in these families to aid further prioritization. Pathway analysis of segregating genes with Combined Annotation Dependent Depletion Tool (CADD) scores >20 was performed using Ingenuity Pathway Analysis software which implicated several candidate genes in pathways involved in B-cell activation and proliferation and in the network of "Cancer, Hematological disease and Immunological Disease." We used the FCVPPv2 for further in silico analyses and prioritized 45 coding and 79 non-coding variants from the three families. Further literature-based analysis allowed us to constrict this list to one rare germline variant each in families I and II and two in family III. Functional studies were conducted on the candidate from family I in a previous study, resulting in the identification and functional validation of a novel heterozygous missense variant in the tumor suppressor gene DICER1 as potential HL predisposition factor. We aim to identify the individual genes responsible for predisposition in the remaining two families and will functionally validate these in further studies.

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The Role of Nonerythroid SpectrinαII in Cancer

Cited by 37 publications

References 115 publications

Isolation and Characterization of Multi-Protein Complexes Enriched in the K-Cl Co-transporter 2 From Brain Plasma Membranes

Isolation and Characterization of Multi-Protein Complexes Enriched in the K-Cl Co-transporter 2 From Brain Plasma Membranes

TheDrosophilaEGFR ligand mSpitz is delivered to cytoplasmic capes at sites of non-canonical RNA export on the nuclear envelopeviathe endosomal system

Identification of Familial Hodgkin Lymphoma Predisposing Genes Using Whole Genome Sequencing

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