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STRN (striatin, calmodulin binding protein)

Written2008-05Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers; CHU Poitiers Hospital, F-86021 Poitiers, France

(Note : for Links provided by Atlas : click)

Identity

Alias_namesstriatin
Alias_symbol (synonym)SG2NA
PPP2R6A
Other aliasMGC125642
HGNC (Hugo) STRN
LocusID (NCBI) 6801
Atlas_Id 44243
Location 2p22.2  [Link to chromosome band 2p22]
Location_base_pair Starts at 37064841 and ends at 37193615 bp from pter ( according to hg19-Feb_2009)  [Mapping STRN.png]
Fusion genes
(updated 2016)
NFIB (9p23) / STRN (2p22.2)STRN (2p22.2) / ALK (2p23.2)STRN (2p22.2) / HEATR5B (2p22.2)
STRN (2p22.2) / MRPL9 (1q21.3)STRN (2p22.2) / PDGFRA (4q12)STRN (2p22.2) / TGFBR2 (3p24.1)
USP49 (6p21.1) / STRN (2p22.2)

DNA/RNA

 
  Figure 1: STRIATIN - STRN (2p12.2) DNA structure - isoforms I and II.
Description The gene spans 118.144 Kb on minus strand (starts at 36 928 976 bp from pter, and ends at: 37 047 119).
Transcription Alternative splicing (see Figure 1): exon 1 of isoform I is truncated in isoform II (136 bases missing), and preceeded by another exon in 5' (81 bases); exon 8 of isoform I (111 bases) is missing in isoform II, according to Ensembl.

Protein

 
  Figure 2: The domains of STRN. Isoform I is shown; amino acids are numbered according to Swiss-Prot description.
Description 780 amino acids (aa), 86.13 KDa (isoform I) and 731 amino acids, 80.76 KDa (isoform II). Striatin contains a high number of domains mediating protein-protein interactions. Domains:
aa 55-63 : Caveolin-binding; aa 53-120 : Coiled-coil; aa 149-166 : Calmodulin-binding; aa 461-500 : WD 1; aa 514-553 : WD 2; aa 567-606 : WD 3; aa 662-701 : WD 4; aa 704-743 : WD 5; aa 750-779 : WD 6 (30 aa only) (Isoform I, according to Swiss-Prot).
- Caveolin-binding domain: To bind caveolin, a caveolin-binding consensus is necessary: ΦXΦXXXXΦ, ΦXXXXΦXXΦ or ΦXΦXXXXΦXXΦ (Φ corresponding to aromatic amino acid) (Couet et al., 1997). Striatin contains the caveolin-binding consensus motif: LHFIQHEWARF, and binds directly caveolin-1 (Gaillard et al., 2001).
- Coiled-coil domain: Coiled-coil domains allow homo- and hetero-oligomerization. Oligomerization of striatin members is an obligatory step for the correct routing of the striatin family members to the dendritic spines (Gaillard et al., 2006).
- Ca2+ -calmodulin binding domain: Striatin binds calmodulin in a calcium-dependent manner. Ca2+ has a pleiotropic effect in cells. In dendritic spines, it plays a crucial role in the induction of most forms of synaptic potentiation and depression. Members of the striatin family could act as Ca2+ sensors in protein complexes, able to drive the delocalization of these complexes in different submembranous micro-domain according to the Ca2+ fluctuations (Benoist et al., 2006).
- WD-repeats (tryptophan-aspartate repeats): tend to form a propeller structure, stable platform that reversibly interacts with several proteins. The WD-repeat domain enables proteins to establish multiple protein-protein interactions. Striatin possesses at least 6 WD-repeats (eight were reported previously).
 
  Figure 3: WD-repeats propeller structure.
Expression Widely expressed (heart, various digestive organs, kidney, and others (Breitman et al., 2008)), but mainly in the nervous system. All members of the striatin family are expressed in the central nervous system and in the peripheral nervous system (Blondeau et al., 2003). Striatin is found in dendrites, on the post-synaptic side, in the post-synaptic densities of neuronal dendritic spines, particularly in the striatum.
 
  Figure 4: ModBase predicted comparative 3D structure (Front / Top / Side). Reproduced courtesy UCSC Genome Browser website.
Localisation Found in the cytosol, and also found associated with membranes.
Function Striatin, like other striatin family members, binds many proteins, and forms multi-protein complexes. Striatin family members are scaffolding proteins involved in signaling and trafficking in a Ca2+ dependant manner, exhibiting a dual role in endocytic process and signaling.
- Relation with caveolins: striatin directly binds caveolin-1 (Gaillard et al., 2001), a palmitoylated protein involved in caveolae and lipid rafts. Caveolins are scaffolding proteins, the main components of caveolae. Caveolae start as plasma membrane pits and form vesicles in the cytoplasm. Caveolae represent one mode of endocytosis (a clathrin independent mode of endocytosis). Caveolins also have the capacity to bind cholesterol, and are involved in signal transduction processes by directly interacting with a great number of signaling proteins such as nitric oxide synthases, G-proteins, protein tyrosine kinases, and H-Ras (Krajewska et al., 2004). Caveolin-1 is concentrated within dendritic spines of synapses in activity.
- Role in synaptic transmission: striatin down regulation in embryonic motoneurones results in the arrest of dendritic growth, but not in axon growth impairement (Bartoli et al., 1999).
Members of the striatin family have been shown to interact with phocein, a protein involved in clathrin- and dynamin-dependent membrane dynamics (Baillat et al., 2001, Haeberle et al., 2006). Phocein has been implicated in vesicular trafficking, acting in particular in the endocytic process in Purkinje cell dendritic spines (Bailly et al., 2007).
The coiled-coil domain of the striatin family members seems crucial for homo- and hetero-oligomerization of these proteins. Striatin family members are often co-expressed in the neurons. The coiled-coil domain also plays an essential role in the targeting of STRN3 within spines (Gaillard et al., 2006).
- Role in the "non-genomic" estrogen-mediated activation of downstream signaling pathways: in vascular endothelial cells, estrogen receptor (ER) alpha is targeted by striatin (or by STRN3, there is a controversy in this) to a module in membrane caveolae that enables estrogen to activate the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3 (PI3K)-Akt kinase pathways, and endothelial NO synthase (eNOS). Striatin (or STRN3) directly binds ER alpha and anchors ER alpha to the membrane and organizes the ER alpha-eNOS membrane signaling complex (Lu et al., 2004) (Note: estrogens also act in a "genomic manner", as transcrition factors, regulating gene expression).
- Cell lines: In NIH3T3 cells, striatin and STRN3 form stable complexes with protein phosphatase 2A (PP2A), a multifunctional serine/threonine phosphatase, critical to many cellular processes (Moreno et al., 2000), including presence in the b-catenin degradation complex, leading to degradation of b-catenin and inhibition of Wnt signaling, but also F-actin binding and regulation and aPKC (a member of the Par complex) regulation.
In HEK293Tcells, striatin binds APC (Breitman et al., 2008). APC is a a multi-function protein e.g.: negative WNT signaling pathway regulation, preventing transcription of Wnt target genes; modulation of the actin cytoskeleton and influence on cell adhesion and cell motility, binding to microtubules inducing stabilization of their ends; interaction with the disks large homologs, which are scaffolding proteins. The APC armadillo repeat domain binds the WD-repeats of striatin and both proteins co-localize at epithelial cell to cell junctions and seem to play a role in junctional organization, since their depletion resulted in a F-actin network fragmentation.
- Neurones and epithelial cells: it may be possible that Striatin and APC (and perhaps PP2A) are involved in the Par complex (PAR-3, PAR-6 and aPKC), a protein complex crucial for neurite, as well as for epithelial cell, polarization (Breitman et al., 2008).
Homology Other members of the striatin family, i.e.: STRN3 (SG2NA) (14q12) and STRN4 (zinedin) (19q13.2), are 80% and 75% homologous to STRN.

Implicated in

Note
  
Entity t(2;4)(p22;q12) in myeloproliferative disease with eosinophilia --> STRN - PDGFRA hybrid gene.
Abnormal Protein The N-term STRN - C-term PDGFRA fusion protein retains the caveolin-binding domain, the coiled-coil domain, and the calmodulin-binding domain, but not the WD-repeats of STRN, fused to a truncated WW-like domain and the kinase domain of PDGFRA; the coiled-coil domain from STRN may act as a dimerization motif that could constitutively activate PDGFRA tyrosine kinase.
  

Bibliography

Molecular cloning and characterization of phocein, a protein found from the Golgi complex to dendritic spines.
Baillat G, Moqrich A, Castets F, Baude A, Bailly Y, Benmerah A, Monneron A.
Mol Biol Cell. 2001 Mar; 12(3): 663-73.
PMID 11251078
 
Phocein: A potential actor in vesicular trafficking at Purkinje cell dendritic spines.
Bailly YJ, Castets F.
Cerebellum. 2007 Feb 23: 1-9.
PMID 17853115
 
Down-regulation of striatin, a neuronal calmodulin-binding protein, impairs rat locomotor activity.
Bartoli M, Ternaux JP, Forni C, Portalier P, Salin P, Amalric M, Monneron A.
J Neurobiol. 1999 Aug; 40(2): 234-43.
PMID 10413453
 
The striatin family: a new signaling platform in dendritic spines.
Benoist M, Gaillard S, Castets F.
J Physiol Paris. 2006 Mar-May;99(2-3):146-53. Epub 2006 Feb 7. (Review)
PMID 16460920
 
Expression and distribution of phocein and members of the striatin family in neurones of rat peripheral ganglia.
Blondeau C, Gaillard S, Ternaux JP, Monneron A, Baude A.
Histochem Cell Biol. 2003 Feb; 119(2): 131-8.
PMID 12610732
 
The armadillo repeat domain of the APC tumor suppressor protein interacts with Striatin family members.
Breitman M, Zilberberg A, Caspi M, Rosin-Arbesfeld R.
Biochim Biophys Acta. 2008 May 3.
PMID 18502210
 
Identification of peptide and protein ligands for the caveolin-scaffolding domain. Implications for the interaction of caveolin with caveolae-associated proteins.
Couet J, Li S, Okamoto T, Ikezu T, Lisanti MP.
J Biol Chem. 1997 Mar 7; 272(10): 6525-33.
PMID 9045678
 
Two novel imatinib-responsive PDGFRA fusion genes in chronic eosinophilic leukaemia.
Curtis CE, Grand FH, Musto P, Clark A, Murphy J, Perla G, Minervini MM, Stewart J, Reiter A, Cross NC.
Br J Haematol. 2007 Jul; 138(1): 77-81.
PMID 17555450
 
Targeting of proteins of the striatin family to dendritic spines: role of the coiled-coil domain.
Gaillard S, Bailly Y, Benoist M, Rakitina T, Kessler JP, Fronzaroli-Molini L, Dargent B, Castets F.
Traffic. 2006 Jan; 7(1): 74-84.
PMID 16445688
 
Immunogold localization of phocein in dendritic spines.
Haeberle AM, Castets F, Bombarde G, Baillat G, Bailly Y.
J Comp Neurol. 2006 Mar 20; 495(3): 336-50.
PMID 16440294
 
Caveolins: structure and function in signal transduction.
Krajewska WM, Maslowska I.
Cell Mol Biol Lett. 2004; 9(2): 195-220. (Review)
PMID 15213803
 
Striatin assembles a membrane signaling complex necessary for rapid, nongenomic activation of endothelial NO synthase by estrogen receptor alpha.
Lu Q, Pallas DC, Surks HK, Baur WE, Mendelsohn ME, Karas RH.
Proc Natl Acad Sci U S A. 2004 Dec 7; 101(49): 17126-31.
PMID 15569929
 
WD40 repeat proteins striatin and S/G(2) nuclear autoantigen are members of a novel family of calmodulin-binding proteins that associate with protein phosphatase 2A.
Moreno CS, Park S, Nelson K, Ashby D, Hubalek F, Lane WS, Pallas DC.
J Biol Chem. 2000 Feb 25; 275(8): 5257-63.
PMID 10681496
 

Citation

This paper should be referenced as such :
Huret, JL
STRN (striatin, calmodulin binding protein)
Atlas Genet Cytogenet Oncol Haematol. 2009;13(4):293-296.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/STRNID44243ch2p22.html


Other Leukemias implicated (Data extracted from papers in the Atlas) [ 4 ]
  del(4)(q12q12) FIP1L1/PDGFRA
ins(9;4)(q33;q12q25) CDK5RAP2/PDGFRA
t(2;4)(p22;q12) STRN/PDGFRA
t(4;12)(q12;p13) PDGFRA/ETV6


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]
  Lung: Translocations in Adenocarcinoma


External links

Nomenclature
HGNC (Hugo)STRN   11424
Cards
AtlasSTRNID44243ch2p22
Entrez_Gene (NCBI)STRN  6801  striatin
AliasesSG2NA
GeneCards (Weizmann)STRN
Ensembl hg19 (Hinxton)ENSG00000115808 [Gene_View]  chr2:37064841-37193615 [Contig_View]  STRN [Vega]
Ensembl hg38 (Hinxton)ENSG00000115808 [Gene_View]  chr2:37064841-37193615 [Contig_View]  STRN [Vega]
ICGC DataPortalENSG00000115808
TCGA cBioPortalSTRN
AceView (NCBI)STRN
Genatlas (Paris)STRN
WikiGenes6801
SOURCE (Princeton)STRN
Genetics Home Reference (NIH)STRN
Genomic and cartography
GoldenPath hg19 (UCSC)STRN  -     chr2:37064841-37193615 -  2p22.2   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)STRN  -     2p22.2   [Description]    (hg38-Dec_2013)
EnsemblSTRN - 2p22.2 [CytoView hg19]  STRN - 2p22.2 [CytoView hg38]
Mapping of homologs : NCBISTRN [Mapview hg19]  STRN [Mapview hg38]
OMIM614765   
Gene and transcription
Genbank (Entrez)AJ223814 AK026934 AK307836 BC015406 BC036416
RefSeq transcript (Entrez)NM_003162
RefSeq genomic (Entrez)NC_000002 NC_018913 NT_022184 NW_004929300
Consensus coding sequences : CCDS (NCBI)STRN
Cluster EST : UnigeneHs.127486 [ NCBI ]
CGAP (NCI)Hs.127486
Alternative Splicing GalleryENSG00000115808
Gene ExpressionSTRN [ NCBI-GEO ]   STRN [ EBI - ARRAY_EXPRESS ]   STRN [ SEEK ]   STRN [ MEM ]
Gene Expression Viewer (FireBrowse)STRN [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)6801
GTEX Portal (Tissue expression)STRN
Protein : pattern, domain, 3D structure
UniProt/SwissProtO43815   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtO43815  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProO43815
Splice isoforms : SwissVarO43815
PhosPhoSitePlusO43815
Domaine pattern : Prosite (Expaxy)WD_REPEATS_1 (PS00678)    WD_REPEATS_2 (PS50082)    WD_REPEATS_REGION (PS50294)   
Domains : Interpro (EBI)G-protein_beta_WD-40_rep    Striatin_N    WD40/YVTN_repeat-like_dom    WD40_repeat    WD40_repeat_CS    WD40_repeat_dom   
Domain families : Pfam (Sanger)Striatin (PF08232)    WD40 (PF00400)   
Domain families : Pfam (NCBI)pfam08232    pfam00400   
Domain families : Smart (EMBL)WD40 (SM00320)  
Conserved Domain (NCBI)STRN
DMDM Disease mutations6801
Blocks (Seattle)STRN
SuperfamilyO43815
Human Protein AtlasENSG00000115808
Peptide AtlasO43815
HPRD18124
IPIIPI00014456   IPI00654594   IPI01012912   
Protein Interaction databases
DIP (DOE-UCLA)O43815
IntAct (EBI)O43815
FunCoupENSG00000115808
BioGRIDSTRN
STRING (EMBL)STRN
ZODIACSTRN
Ontologies - Pathways
QuickGOO43815
Ontology : AmiGOprotein phosphatase type 2A complex  protein binding  calmodulin binding  calmodulin binding  cytoplasm  bicellular tight junction  locomotory behavior  negative regulation of cell proliferation  postsynaptic density  membrane  Wnt signaling pathway  dendrite development  estrogen receptor binding  protein complex binding  neuronal cell body  dendritic spine  postsynaptic membrane  protein phosphatase 2A binding  armadillo repeat domain binding  bicellular tight junction assembly  
Ontology : EGO-EBIprotein phosphatase type 2A complex  protein binding  calmodulin binding  calmodulin binding  cytoplasm  bicellular tight junction  locomotory behavior  negative regulation of cell proliferation  postsynaptic density  membrane  Wnt signaling pathway  dendrite development  estrogen receptor binding  protein complex binding  neuronal cell body  dendritic spine  postsynaptic membrane  protein phosphatase 2A binding  armadillo repeat domain binding  bicellular tight junction assembly  
NDEx NetworkSTRN
Atlas of Cancer Signalling NetworkSTRN
Wikipedia pathwaysSTRN
Orthology - Evolution
OrthoDB6801
GeneTree (enSembl)ENSG00000115808
Phylogenetic Trees/Animal Genes : TreeFamSTRN
HOVERGENO43815
HOGENOMO43815
Homologs : HomoloGeneSTRN
Homology/Alignments : Family Browser (UCSC)STRN
Gene fusions - Rearrangements
Fusion : MitelmanNFIB/STRN [9p23/2p22.2]  [t(2;9)(p22;p22)]  
Fusion : MitelmanSTRN/ALK [2p22.2/2p23.2]  [del(2)(p22p23)]  [t(2;2)(p22;p23)]  
Fusion : MitelmanSTRN/HEATR5B [2p22.2/2p22.2]  [t(2;2)(p22;p22)]  
Fusion : MitelmanSTRN/PDGFRA [2p22.2/4q12]  [t(2;4)(p22;q12)]  
Fusion : MitelmanUSP49/STRN [6p21.1/2p22.2]  [t(2;6)(p22;p21)]  
Fusion : COSMICSTRN [2p22.2]  -  ALK [2p23.2]  [fusion_1430]  [fusion_1431]  [fusion_1538]  [fusion_1669]  [fusion_1670]  
Fusion: TCGANFIB 9p23 STRN 2p22.2 BRCA
Fusion: TCGASTRN 2p22.2 ALK 2p23.2 THCA
Fusion: TCGASTRN 2p22.2 HEATR5B 2p22.2 BRCA
Fusion: TCGAUSP49 6p21.1 STRN 2p22.2 BRCA
Fusion : TICdbSTRN [2p22.2]  -  PDGFRA [4q12]
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerSTRN [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)STRN
dbVarSTRN
ClinVarSTRN
1000_GenomesSTRN 
Exome Variant ServerSTRN
ExAC (Exome Aggregation Consortium)STRN (select the gene name)
Genetic variants : HAPMAP6801
Genomic Variants (DGV)STRN [DGVbeta]
DECIPHER (Syndromes)2:37064841-37193615  ENSG00000115808
CONAN: Copy Number AnalysisSTRN 
Mutations
ICGC Data PortalSTRN 
TCGA Data PortalSTRN 
Broad Tumor PortalSTRN
OASIS PortalSTRN [ Somatic mutations - Copy number]
Cancer Gene: CensusSTRN 
Somatic Mutations in Cancer : COSMICSTRN  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDSTRN
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch STRN
DgiDB (Drug Gene Interaction Database)STRN
DoCM (Curated mutations)STRN (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)STRN (select a term)
intoGenSTRN
NCG5 (London)STRN
Cancer3DSTRN(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM614765   
Orphanet
MedgenSTRN
Genetic Testing Registry STRN
NextProtO43815 [Medical]
TSGene6801
GENETestsSTRN
Huge Navigator STRN [HugePedia]
snp3D : Map Gene to Disease6801
BioCentury BCIQSTRN
ClinGenSTRN
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD6801
Chemical/Pharm GKB GenePA36224
Clinical trialSTRN
Miscellaneous
canSAR (ICR)STRN (select the gene name)
Probes
Litterature
PubMed44 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineSTRN
EVEXSTRN
GoPubMedSTRN
iHOPSTRN
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Wed Apr 12 11:40:18 CEST 2017

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