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FMNL1 (formin like 1)

Written2016-10Matheus Rodrigues Lopes, Patricia Favaro
Hematology and Hemotherapy Center, University of Campinas - UNICAMP, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas São Paulo (MRL, PF), MRL Presently at Federal University of Vale do São Francisco at Paulo Afonso, Bahia; Department of Biological Sciences, Federal University of São Paulo (PF), Diadema, São Paulo, Brazil. matheuslopesbio@gmail.com, favaropb@gmail.com

Abstract Formin-like 1 (FMNL1) is a member of the Formin protein family, which are regulators of actin and microtubule cytoskeletal dynamics. FMNL1 belongs to the subfamily of formins knows as Diaphanous-related formins (DRF) and is involved in processes such as phagocytosis, cell adhesion, podosome dynamics, cell migration, cytokinesis, and polarity control. It has been suggested that spatial and temporal regulation of FMNL1 is controlled by small Rho GTPases. The present review contains data on FMNL1 DNA/RNA, protein encoded and function.

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Identity

Alias_namesC17orf1B
FMNL
formin-like
formin-like 1
Alias_symbol (synonym)C17orf1
Other aliasFormin-related protein in leukocytes (FRL1)
FRL alpha
HGNC (Hugo) FMNL1
LocusID (NCBI) 752
Atlas_Id 46313
Location 17q21.31  [Link to chromosome band 17q21]
Location_base_pair Starts at 45221925 and ends at 45247316 bp from pter ( according to hg19-Feb_2009)  [Mapping FMNL1.png]

DNA/RNA

Description FMNL1 full-length cDNA (Favaro et al., 2003) was obtained from the EST IL5-MT0208-210201-356-f01 (GenBank Accession No. BI028593), generated from the Human Cancer Genome Project (Dias Neto et al., 2000). The entire FMNL1 gene is located in chromosome 17 (17q21) and has a size of approximately 25.8 Kb (start: 45221444 and end: 45247320 bp; orientation: Plus strand) and contains 17 exons. The FMNL1 cDNA contains 3973 bp and is located in chromosome 17 (17q21).

Protein

 
  Figure 1. Domain structure of FMNL1. Amino acid positions are identified. GBD; GTPase binding domain, DID; Diaphanous inhibitory domain; DD; dimerization domain. FH1 and FH2; Formin homology 1 and 2 domain. DAD; Diaphanous autoregulatory domain.
Description Formin proteins are characterized by a unique and highly conserved C-terminal formin homology (FH) 2 domain, responsible for its interaction with actin (Wallar and Alberts, 2003; Higgs, 2005). Diaphanous-related formins (DRF) are characterized by regulatory domains at the N-terminus, including the GTPase binding domain (GBD), Diaphanous inhibitory domain (DID), and dimerization domain (DD), and a single C-terminal Diaphanous autoregulatory domain (DAD) (Figure 1). DRFs are regulated by an autoinhibitory interaction of DAD with DID (Li and Higgs, 2003). This autoinhibition is relieved through binding of an activated RhoGTPase to the GBD, resulting in activation of formin to polymerize actin filaments (Kuhn and Geyer, 2014)(Figure 2).
 
  Figure 2. Schematic model of regulation of DRF by RhoGTPases. DRF are autoinhibited in an inactivated state by the interaction of DAD with DID. Upon the interaction of an activated Rho GTPase with the GBD, the C-terminal autoregulatory domain is displaced from its N-terminal recognition site, resulting in the activation of formin and consequently the polymerization of actin filaments. Adapted from (Alberts, 2002).
Expression In normal tissues, FMNL1 expression is restricted to peripheral blood mononuclear and homing tissues such as thymus, spleen, lymph nodes and bone marrow (Favaro et al., 2003; Schuster et al., 2007). In bone marrow, FMNL1 expression was restricted to myeloid cells and in lymph nodes, mature lymphocytes stain strongly for FMNL1 (Gardberg et al., 2014).
FMNL1 is highly expressed in a variety of hematopoietic malignancies, including cells from patients with lymphoid and myeloid leukemias and non-Hodgkin's lymphomas, as well as malignant lymphoid and myeloid cell lines and in renal carcinoma cell lines (Favaro et al., 2003; Favaro et al., 2006; Schuster et al., 2007). Recently, Gardberg et al reported that FMNL1 to be also expressed in smooth muscle cells and myoepithelial cells (Gardberg et al., 2014).
Localisation Immunohistochemical analyses have shown that FMNL1 staining is cytoplasmatic (Gardberg et al., 2014).
Function Many functions have been attributed to FMNL1, such as cell adhesion, cytokinesis, cell polarization and migration in mitosis (Yayoshi-Yamamoto et al., 2000; Seth et al., 2006; Esue et al., 2008; Mersich et al., 2010). The silencing of FMNL1 reduces cell proliferation as well as migration of human leukemia cells and tumor growth (Favaro et al., 2013). FMNL1 is needed for cytotoxicity, polarization and maintenance of the Golgi complex in T-cells (Gomez et al., 2007; Colon-Franco et al., 2011). FMNL1 is involved in podosome dynamics in macrophage cell lines (Mersich et al., 2010) and a new splice variant of FMNL1, FMNL1γ, has been reported to induce polarized membrane nonapoptotic blebbing (Han et al., 2009). During mouse oocyte meiotic maturation, FMNL1 has shown to affect both actin dynamics and spindle formation, through a RHOA -FMNL1- GOLGA2 (GM130) pathway, leading to oocyte polar body extrusion (Wang et al., 2015; Yin and Sun, 2015)
Homology FMNL1 shares homology with that of the other members of the formin protein family. FMNL1 also has a high homology among different species (Table 1).

Table 1. Comparative identity of human FMNL1 with other species

% Identity for:Homo sapiens FMNL1Symbol

Protein

DNA

vs. P. troglodytesFMNL1

99.0

99.0

vs. M. mulattaFMNL1

98.0

96.0

vs. C. jacchusFMNL1

95.0

95.0

vs. N. galiliFmnl1

94.0

88.0

vs. B. taurusFMNL1

93.0

86.0

vs. M. musculusFmnl1

93.0

85.0

vs. M. putoriusFMNL1

91.0

88.0

vs. C. lupusFMNL1

91.0

87.0

vs. R. norvegicusFmnl1

89.0

84.0

vs. G. gallusFMNL1

72.0

86.0

vs. I. punctalusfmnl1

69.0

82.0


(Source: http://www.ncbi.nlm.nih.gov/homologene)

Mutations

Somatic Recurrent mutations in the FMNL1 gene are rare, and 123 substitution missense, 4 substitution nonsense, 57 substitution synonymous, 5 insertion inframe, 1 insertion frameshift, 9 deletions inframe and 3 deletion frameshift mutations are reported in COSMIC (Catalogue of somatic mutations in cancer; http://cancer.sanger.ac.uk/cancergenome/projects/cosmic).

Implicated in

  
Entity T-cell non-Hodgkin's lymphoma
Note A study performed in 54 frozen biopsies of T non-Hodgkin's lymphoma (NHL) patients and five reactive lymph nodes showed that FMNL1 protein expression was detected in all samples. However, FMNL1 expression was highest in the T-cell NHL, when compared with others NHL (follicular NHL and diffuse large B-cell NHL) and reactive lymph nodes (Favaro et al., 2006).
  
  
Entity Leukemia
Note FMNL1 protein is overexpressed in malignant cells from patients with lymphoid and myeloid leukemias, including chronic lymphocytic leukemia (CLL), acute B- and T-lymphoblastic leukemia and acute myeloid leukemia (Krackhardt et al., 2002; Favaro et al., 2003; Schuster et al., 2007). These findings are consistent with FMNL1 expression in human leukemic cell lines and also with a large-scale meta-analysis of gene expression in humans (A-AFFY-33, array platform) (Lukk et al., 2010; Favaro et al., 2013).
  
  
Entity Breast cancer
Note Eight basal type breast cancer samples were tested for FMNL1 expression. In three cases, FMNL1 expression was restricted to inflammatory cells and in five samples, FMNL1 staining was observed in a subset of the malignant epithelial cells (Gardberg et al., 2014).
  

To be noted

Allorestricted MHC class I-restricted T cell receptor (TCR) with specificity for FMNL1 and potent activity against CLL cells were isolated (Schuster et al., 2007). Recently, MHC class-II-restricted CD4+ T cells and TCR with specificity for leukaemia antigens, including FMNL1 were also isolated (Weigand et al., 2012)..

Bibliography

Diaphanous-related Formin homology proteins
Alberts AS
Curr Biol 2002 Dec 10;12(23):R796
PMID 12477401
 
Dynamic remodeling of the actin cytoskeleton by FMNL1γ is required for structural maintenance of the Golgi complex
Colón-Franco JM, Gomez TS, Billadeau DD
J Cell Sci 2011 Sep 15;124(Pt 18):3118-26
PMID 21868368
 
Shotgun sequencing of the human transcriptome with ORF expressed sequence tags
Dias Neto E, Correa RG, Verjovski-Almeida S, Briones MR, Nagai MA, da Silva W Jr, Zago MA, Bordin S, Costa FF, Goldman GH, Carvalho AF, Matsukuma A, Baia GS, Simpson DH, Brunstein A, de Oliveira PS, Bucher P, Jongeneel CV, O'Hare MJ, Soares F, Brentani RR, Reis LF, de Souza SJ, Simpson AJ
Proc Natl Acad Sci U S A 2000 Mar 28;97(7):3491-6
PMID 10737800
 
The filamentous actin cross-linking/bundling activity of mammalian formins
Esue O, Harris ES, Higgs HN, Wirtz D
J Mol Biol 2008 Dec 12;384(2):324-34
PMID 18835565
 
FMNL1 promotes proliferation and migration of leukemia cells
Favaro P, Traina F, Machado-Neto JA, Lazarini M, Lopes MR, Pereira JK, Costa FF, Infante E, Ridley AJ, Saad ST
J Leukoc Biol 2013 Sep;94(3):503-12
PMID 23801653
 
High expression of FMNL1 protein in T non-Hodgkin's lymphomas
Favaro PM, Traina F, Vassallo J, Brousset P, Delsol G, Costa FF, Saad ST
Leuk Res 2006 Jun;30(6):735-8
PMID 16494944
 
Human leukocyte formin: a novel protein expressed in lymphoid malignancies and associated with Akt
Favaro PM, de Souza Medina S, Traina F, Bassères DS, Costa FF, Saad ST
Biochem Biophys Res Commun 2003 Nov 14;311(2):365-71
PMID 14592423
 
Characterization of Leukocyte Formin FMNL1 Expression in Human Tissues
Gardberg M, Heuser VD, Iljin K, Kampf C, Uhlen M, Carpén O
J Histochem Cytochem 2014 Apr 3;62(6):460-470
PMID 24700756
 
Formins regulate the actin-related protein 2/3 complex-independent polarization of the centrosome to the immunological synapse
Gomez TS, Kumar K, Medeiros RB, Shimizu Y, Leibson PJ, Billadeau DD
Immunity 2007 Feb;26(2):177-90
PMID 17306570
 
Formin-like 1 (FMNL1) is regulated by N-terminal myristoylation and induces polarized membrane blebbing
Han Y, Eppinger E, Schuster IG, Weigand LU, Liang X, Kremmer E, Peschel C, Krackhardt AM
J Biol Chem 2009 Nov 27;284(48):33409-17
PMID 19815554
 
Formin proteins: a domain-based approach
Higgs HN
Trends Biochem Sci 2005 Jun;30(6):342-53
PMID 15950879
 
Formins as effector proteins of Rho GTPases
Kühn S, Geyer M
Small GTPases 2014;5:e29513
PMID 24914801
 
Identification of tumor-associated antigens in chronic lymphocytic leukemia by SEREX
Krackhardt AM, Witzens M, Harig S, Hodi FS, Zauls AJ, Chessia M, Barrett P, Gribben JG
Blood 2002 Sep 15;100(6):2123-31
PMID 12200376
 
The mouse Formin mDia1 is a potent actin nucleation factor regulated by autoinhibition
Li F, Higgs HN
Curr Biol 2003 Aug 5;13(15):1335-40
PMID 12906795
 
A global map of human gene expression
Lukk M, Kapushesky M, Nikkilä J, Parkinson H, Goncalves A, Huber W, Ukkonen E, Brazma A
Nat Biotechnol 2010 Apr;28(4):322-4
PMID 20379172
 
The formin FRL1 (FMNL1) is an essential component of macrophage podosomes
Mersich AT, Miller MR, Chkourko H, Blystone SD
Cytoskeleton (Hoboken) 2010 Sep;67(9):573-85
PMID 20617518
 
Allorestricted T cells with specificity for the FMNL1-derived peptide PP2 have potent antitumor activity against hematologic and other malignancies
Schuster IG, Busch DH, Eppinger E, Kremmer E, Milosevic S, Hennard C, Kuttler C, Ellwart JW, Frankenberger B, Nössner E, Salat C, Bogner C, Borkhardt A, Kolb HJ, Krackhardt AM
Blood 2007 Oct 15;110(8):2931-9
PMID 17626842
 
Autoinhibition regulates cellular localization and actin assembly activity of the diaphanous-related formins FRLalpha and mDia1
Seth A, Otomo C, Rosen MK
J Cell Biol 2006 Aug 28;174(5):701-13
PMID 16943183
 
The formins: active scaffolds that remodel the cytoskeleton
Wallar BJ, Alberts AS
Trends Cell Biol 2003 Aug;13(8):435-46
PMID 12888296
 
RhoA-mediated FMNL1 regulates GM130 for actin assembly and phosphorylates MAPK for spindle formation in mouse oocyte meiosis
Wang F, Zhang L, Duan X, Zhang GL, Wang ZB, Wang Q, Xiong B, Sun SC
Cell Cycle 2015;14(17):2835-43
PMID 26083584
 
Isolation of human MHC class II-restricted T cell receptors from the autologous T-cell repertoire with potent anti-leukaemic reactivity
Weigand LU, Liang X, Schmied S, Mall S, Klar R, Stötzer OJ, Salat C, Götze K, Mautner J, Peschel C, Krackhardt AM
Immunology 2012 Nov;137(3):226-38
PMID 23025755
 
FRL, a novel formin-related protein, binds to Rac and regulates cell motility and survival of macrophages
Yayoshi-Yamamoto S, Taniuchi I, Watanabe T
Mol Cell Biol 2000 Sep;20(18):6872-81
PMID 10958683
 
FMNL1, a key regulator for asymmetric cell division
Yin S, Sun QY
Cell Cycle 2015;14(18):2879-80
PMID 26301502
 

Citation

This paper should be referenced as such :
Rodrigues Lopes, Favaro P
FMNL1 (formin like 1);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/FMNL1ID46313ch17q21.html


External links

Nomenclature
HGNC (Hugo)FMNL1   1212
Cards
AtlasFMNL1ID46313ch17q21
Entrez_Gene (NCBI)FMNL1  752  formin like 1
AliasesC17orf1; C17orf1B; FHOD4; FMNL; 
KW-13
GeneCards (Weizmann)FMNL1
Ensembl hg19 (Hinxton)ENSG00000184922 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000184922 [Gene_View]  chr17:45221925-45247316 [Contig_View]  FMNL1 [Vega]
ICGC DataPortalENSG00000184922
TCGA cBioPortalFMNL1
AceView (NCBI)FMNL1
Genatlas (Paris)FMNL1
WikiGenes752
SOURCE (Princeton)FMNL1
Genetics Home Reference (NIH)FMNL1
Genomic and cartography
GoldenPath hg38 (UCSC)FMNL1  -     chr17:45221925-45247316 +  17q21.31   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)FMNL1  -     17q21.31   [Description]    (hg19-Feb_2009)
EnsemblFMNL1 - 17q21.31 [CytoView hg19]  FMNL1 - 17q21.31 [CytoView hg38]
Mapping of homologs : NCBIFMNL1 [Mapview hg19]  FMNL1 [Mapview hg38]
OMIM604656   
Gene and transcription
Genbank (Entrez)###############################################################################################################################################################################################################################################################
RefSeq transcript (Entrez)NM_005892
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)FMNL1
Cluster EST : UnigeneHs.729912 [ NCBI ]
CGAP (NCI)Hs.729912
Alternative Splicing GalleryENSG00000184922
Gene ExpressionFMNL1 [ NCBI-GEO ]   FMNL1 [ EBI - ARRAY_EXPRESS ]   FMNL1 [ SEEK ]   FMNL1 [ MEM ]
Gene Expression Viewer (FireBrowse)FMNL1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)752
GTEX Portal (Tissue expression)FMNL1
Protein : pattern, domain, 3D structure
UniProt/SwissProtO95466   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtO95466  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProO95466
Splice isoforms : SwissVarO95466
PhosPhoSitePlusO95466
Domaine pattern : Prosite (Expaxy)DAD (PS51231)    FH2 (PS51444)    GBD_FH3 (PS51232)   
Domains : Interpro (EBI)ARM-type_fold    DAD_dom    FH2_Formin    FH3_dom    FMNL1    GBD/FH3_dom    GTPase-bd   
Domain families : Pfam (Sanger)Drf_FH3 (PF06367)    Drf_GBD (PF06371)    FH2 (PF02181)   
Domain families : Pfam (NCBI)pfam06367    pfam06371    pfam02181   
Domain families : Smart (EMBL)Drf_FH3 (SM01139)  Drf_GBD (SM01140)  FH2 (SM00498)  
Conserved Domain (NCBI)FMNL1
DMDM Disease mutations752
Blocks (Seattle)FMNL1
PDB (SRS)4YDH   
PDB (PDBSum)4YDH   
PDB (IMB)4YDH   
PDB (RSDB)4YDH   
Structural Biology KnowledgeBase4YDH   
SCOP (Structural Classification of Proteins)4YDH   
CATH (Classification of proteins structures)4YDH   
SuperfamilyO95466
Human Protein AtlasENSG00000184922
Peptide AtlasO95466
HPRD06876
IPIIPI00163516   IPI00025202   IPI01013683   IPI00442349   
Protein Interaction databases
DIP (DOE-UCLA)O95466
IntAct (EBI)O95466
FunCoupENSG00000184922
BioGRIDFMNL1
STRING (EMBL)FMNL1
ZODIACFMNL1
Ontologies - Pathways
QuickGOO95466
Ontology : AmiGOmolecular_function  protein binding  profilin binding  cytosol  cytosol  cytosol  plasma membrane  cell cortex  substrate-dependent cell migration  regulation of cell shape  membrane  cortical actin cytoskeleton organization  bleb  GTPase activating protein binding  phagocytic vesicle  Rac GTPase binding  actin filament severing  actin filament binding  extracellular exosome  
Ontology : EGO-EBImolecular_function  protein binding  profilin binding  cytosol  cytosol  cytosol  plasma membrane  cell cortex  substrate-dependent cell migration  regulation of cell shape  membrane  cortical actin cytoskeleton organization  bleb  GTPase activating protein binding  phagocytic vesicle  Rac GTPase binding  actin filament severing  actin filament binding  extracellular exosome  
REACTOMEO95466 [protein]
REACTOME PathwaysR-HSA-5663220 [pathway]   
NDEx NetworkFMNL1
Atlas of Cancer Signalling NetworkFMNL1
Wikipedia pathwaysFMNL1
Orthology - Evolution
OrthoDB752
GeneTree (enSembl)ENSG00000184922
Phylogenetic Trees/Animal Genes : TreeFamFMNL1
HOVERGENO95466
HOGENOMO95466
Homologs : HomoloGeneFMNL1
Homology/Alignments : Family Browser (UCSC)FMNL1
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerFMNL1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)FMNL1
dbVarFMNL1
ClinVarFMNL1
1000_GenomesFMNL1 
Exome Variant ServerFMNL1
ExAC (Exome Aggregation Consortium)FMNL1 (select the gene name)
Genetic variants : HAPMAP752
Genomic Variants (DGV)FMNL1 [DGVbeta]
DECIPHERFMNL1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisFMNL1 
Mutations
ICGC Data PortalFMNL1 
TCGA Data PortalFMNL1 
Broad Tumor PortalFMNL1
OASIS PortalFMNL1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICFMNL1  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDFMNL1
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 FMNL1
DgiDB (Drug Gene Interaction Database)FMNL1
DoCM (Curated mutations)FMNL1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)FMNL1 (select a term)
intoGenFMNL1
NCG5 (London)FMNL1
Cancer3DFMNL1(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM604656   
Orphanet
MedgenFMNL1
Genetic Testing Registry FMNL1
NextProtO95466 [Medical]
TSGene752
GENETestsFMNL1
Target ValidationFMNL1
Huge Navigator FMNL1 [HugePedia]
snp3D : Map Gene to Disease752
BioCentury BCIQFMNL1
ClinGenFMNL1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD752
Chemical/Pharm GKB GenePA28186
Clinical trialFMNL1
Miscellaneous
canSAR (ICR)FMNL1 (select the gene name)
Probes
Litterature
PubMed28 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineFMNL1
EVEXFMNL1
GoPubMedFMNL1
iHOPFMNL1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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