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KSR1 (kinase suppressor of ras 1)

Written2011-02Mario Fernandez, Robert Lewis
Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_namesKSR
kinase suppressor of ras
Alias_symbol (synonym)RSU2
Other alias
HGNC (Hugo) KSR1
LocusID (NCBI) 8844
Atlas_Id 41107
Location 17q11.1  [Link to chromosome band 17q11]
Location_base_pair Starts at 27472010 and ends at 27623692 bp from pter ( according to hg19-Feb_2009)  [Mapping KSR1.png]
Local_order From centromere to telomere on 17q11.2, the KSR1 gene is flanked by: EOE1, EVI2A, JJAZ1, KNO3, KRT24, KSR1, LGALS9, LYZL6, MIR144, MIR451 (NCBI).
Fusion genes
(updated 2016)
AGPAT3 (21q22.3) / KSR1 (17q11.1)CDR2L (17q25.1) / KSR1 (17q11.1)CFAP46 (10q26.3) / KSR1 (17q11.1)
CHD9 (16q12.2) / KSR1 (17q11.1)CYTH1 (17q25.3) / KSR1 (17q11.1)KSR1 (17q11.1) / EFCAB5 (17q11.2)
KSR1 (17q11.1) / KSR1 (17q11.1)KSR1 (17q11.1) / LGALS9 (17q11.2)KSR1 (17q11.1) / MSI2 (17q22)
KSR1 (17q11.1) / PIPOX (17q11.2)KSR1 (17q11.1) / TENM1 (Xq25)MKS1 (17q22) / KSR1 (17q11.1)

DNA/RNA

 
  KSR1 contains 17 exons, 154426 base pairs.
Description The KSR1 gene was discovered in D. melanogaster and is highly conserved along the evolutionary tree through H. sapiens.
Transcription Transcription can produce two different mRNA transcripts. The KSR1 is expressed in the thymus, bone marrow, brain, heart, kidney, lung, liver, pancreas, mammary gland, ovary, testis and muscle.
Pseudogene No known pseudogenes.

Protein

Note Belongs to the KSR family of proteins.
 
  The KSR1 protein contains five conserved areas (CA). The CA1 region is unique to KSR1 protein; the CA2 region is a proline-rich region; the CA3 region is implicated in the Ras-induced plasma membrane localization; the CA4 region is a serine/threonine rich region and contains the MAPK docking site (FXFP); and the putative kinase domain (CA5), which contains an amino acid variation in subdomain II that suggests that this protein is catalytically inert. The KSR1 protein is composed of 921 amino acids.
Description The KSR1 protein is 921 kDa. There have been 15 phosphorylation sites identified.
Expression Brain, kidney, lung, pancreas, ovaries, testis, breast.
Localisation Sequestered in the cytoplasm in quiescents cells. Upon stimulation, KSR1 protein localizes to the plasma membrane.
Function Acts as a scaffold for the Raf/MEK/ERK kinase cascade.
Homology R. norvegicus KSR1 (91.85%), M. musculus KSR1 (91.3%), C. familians KSR1 (93.62%), G. gallus KSR1 (76.39%), D. reno KSR1 (67.85%), D. Melanogaster KSR (41.06%), C. elegans KSR1 (35.37%), X. laevis KSR1 (76.06%).

Mutations

Note There have been no prominent germinal or somatic mutations identified.

Implicated in

Note
  
Entity Cancer
Note KSR1 has not been found to be upregulated or downregulated in tumors. However, studies in KSR1 knockout mice showed that the mice were less susceptible to papilloma virus driven tumors, indicating that KSR1 is required for Ras-mediated oncogenesis.
  

To be noted

KSR1 is primarily recognized as a scaffold for the Raf/MEK/ERK kinase cascade. However, there are several published studies that sustain that KSR1 has catalytic activity. KSR1 is recognized as a pseudokinase, since mammalian KSR1 does not possess the lysine responsible for ATP orientation and hydrolysis in the putative kinase domain. This lysine is present in C. elegans and D. melanogaster, but mutation of this site did not affect activation of the Raf/MEK/ERK pathway. A recent publication (Rajakulendran et al., 2009) showed that KSR1 dimerization via its kinase domain to Raf facilitated the activation of Raf without KSR1 catalytic activity. It remains possible that KSR1 proteins have catalytic activity based on a yet to be identified novel mechanism.

Bibliography

Ras subcellular localization defines extracellular signal-regulated kinase 1 and 2 substrate specificity through distinct utilization of scaffold proteins.
Casar B, Arozarena I, Sanz-Moreno V, Pinto A, Agudo-Ibanez L, Marais R, Lewis RE, Berciano MT, Crespo P.
Mol Cell Biol. 2009 Mar;29(5):1338-53. Epub 2008 Dec 29.
PMID 19114553
 
IMP modulates KSR1-dependent multivalent complex formation to specify ERK1/2 pathway activation and response thresholds.
Chen C, Lewis RE, White MA.
J Biol Chem. 2008 May 9;283(19):12789-96. Epub 2008 Mar 10.
PMID 18332145
 
The MAPK scaffold kinase suppressor of Ras is involved in ERK activation by stress and proinflammatory cytokines and induction of arthritis.
Fusello AM, Mandik-Nayak L, Shih F, Lewis RE, Allen PM, Shaw AS.
J Immunol. 2006 Nov 1;177(9):6152-8.
PMID 17056543
 
Expression of kinase suppressor of Ras in the normal adult and embryonic mouse.
Giblett SM, Lloyd DJ, Light Y, Marais R, Pritchard CA.
Cell Growth Differ. 2002 Jul;13(7):307-13.
PMID 12133899
 
The mitogen-activated protein kinase scaffold KSR1 is required for recruitment of extracellular signal-regulated kinase to the immunological synapse.
Giurisato E, Lin J, Harding A, Cerutti E, Cella M, Lewis RE, Colonna M, Shaw AS.
Mol Cell Biol. 2009 Mar;29(6):1554-64. Epub 2009 Jan 12.
PMID 19139278
 
Expression of kinase suppressor of Ras1 enhances cisplatin-induced extracellular signal-regulated kinase activation and cisplatin sensitivity.
Kim M, Yan Y, Kortum RL, Stoeger SM, Sgagias MK, Lee K, Lewis RE, Cowan KH.
Cancer Res. 2005 May 15;65(10):3986-92.
PMID 15899786
 
The ksr-1 gene encodes a novel protein kinase involved in Ras-mediated signaling in C. elegans.
Kornfeld K, Hom DB, Horvitz HR.
Cell. 1995 Dec 15;83(6):903-13.
PMID 8521514
 
The molecular scaffold kinase suppressor of Ras 1 (KSR1) regulates adipogenesis.
Kortum RL, Costanzo DL, Haferbier J, Schreiner SJ, Razidlo GL, Wu MH, Volle DJ, Mori T, Sakaue H, Chaika NV, Chaika OV, Lewis RE.
Mol Cell Biol. 2005 Sep;25(17):7592-604.
PMID 16107706
 
The molecular scaffold kinase suppressor of Ras 1 is a modifier of RasV12-induced and replicative senescence.
Kortum RL, Johnson HJ, Costanzo DL, Volle DJ, Razidlo GL, Fusello AM, Shaw AS, Lewis RE.
Mol Cell Biol. 2006 Mar;26(6):2202-14.
PMID 16507997
 
The molecular scaffold KSR1 regulates the proliferative and oncogenic potential of cells.
Kortum RL, Lewis RE.
Mol Cell Biol. 2004 May;24(10):4407-16.
PMID 15121859
 
Kinase suppressor of Ras couples Ras to the ERK cascade during T cell development.
Laurent MN, Ramirez DM, Alberola-Ila J.
J Immunol. 2004 Jul 15;173(2):986-92.
PMID 15240686
 
Deficiency of kinase suppressor of Ras1 prevents oncogenic ras signaling in mice.
Lozano J, Xing R, Cai Z, Jensen HL, Trempus C, Mark W, Cannon R, Kolesnick R.
Cancer Res. 2003 Jul 15;63(14):4232-8.
PMID 12874031
 
Caspase-dependent cleavage disrupts the ERK cascade scaffolding function of KSR1.
McKay MM, Morrison DK.
J Biol Chem. 2007 Sep 7;282(36):26225-34. Epub 2007 Jul 5.
PMID 17613518
 
Signaling dynamics of the KSR1 scaffold complex.
McKay MM, Ritt DA, Morrison DK.
Proc Natl Acad Sci U S A. 2009 Jul 7;106(27):11022-7. Epub 2009 Jun 18.
PMID 19541618
 
KSR stimulates Raf-1 activity in a kinase-independent manner.
Michaud NR, Therrien M, Cacace A, Edsall LC, Spiegel S, Rubin GM, Morrison DK.
Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):12792-6.
PMID 9371754
 
Identification of B-KSR1, a novel brain-specific isoform of KSR1 that functions in neuronal signaling.
Muller J, Cacace AM, Lyons WE, McGill CB, Morrison DK.
Mol Cell Biol. 2000 Aug;20(15):5529-39.
PMID 10891492
 
C-TAK1 regulates Ras signaling by phosphorylating the MAPK scaffold, KSR1.
Muller J, Ory S, Copeland T, Piwnica-Worms H, Morrison DK.
Mol Cell. 2001 Nov;8(5):983-93.
PMID 11741534
 
Kinase suppressor of Ras (KSR) is a scaffold which facilitates mitogen-activated protein kinase activation in vivo.
Nguyen A, Burack WR, Stock JL, Kortum R, Chaika OV, Afkarian M, Muller WJ, Murphy KM, Morrison DK, Lewis RE, McNeish J, Shaw AS.
Mol Cell Biol. 2002 May;22(9):3035-45.
PMID 11940661
 
Protein phosphatase 2A positively regulates Ras signaling by dephosphorylating KSR1 and Raf-1 on critical 14-3-3 binding sites.
Ory S, Zhou M, Conrads TP, Veenstra TD, Morrison DK.
Curr Biol. 2003 Aug 19;13(16):1356-64.
PMID 12932319
 
A dimerization-dependent mechanism drives RAF catalytic activation.
Rajakulendran T, Sahmi M, Lefrancois M, Sicheri F, Therrien M.
Nature. 2009 Sep 24;461(7263):542-5. Epub 2009 Sep 2.
PMID 19727074
 
KSR1 is required for cell cycle reinitiation following DNA damage.
Razidlo GL, Johnson HJ, Stoeger SM, Cowan KH, Bessho T, Lewis RE.
J Biol Chem. 2009 Mar 13;284(11):6705-15. Epub 2009 Jan 15.
PMID 19147494
 
CK2 Is a component of the KSR1 scaffold complex that contributes to Raf kinase activation.
Ritt DA, Zhou M, Conrads TP, Veenstra TD, Copeland TD, Morrison DK.
Curr Biol. 2007 Jan 23;17(2):179-84. Epub 2006 Dec 14.
PMID 17174095
 
KSR is a scaffold required for activation of the ERK/MAPK module.
Roy F, Laberge G, Douziech M, Ferland-McCollough D, Therrien M.
Genes Dev. 2002 Feb 15;16(4):427-38.
PMID 11850406
 
Nm23-H1 metastasis suppressor expression level influences the binding properties, stability, and function of the kinase suppressor of Ras1 (KSR1) Erk scaffold in breast carcinoma cells.
Salerno M, Palmieri D, Bouadis A, Halverson D, Steeg PS.
Mol Cell Biol. 2005 Feb;25(4):1379-88.
PMID 15684389
 
The C. elegans ksr-1 gene encodes a novel Raf-related kinase involved in Ras-mediated signal transduction.
Sundaram M, Han M.
Cell. 1995 Dec 15;83(6):889-901.
PMID 8521513
 
KSR modulates signal propagation within the MAPK cascade.
Therrien M, Michaud NR, Rubin GM, Morrison DK.
Genes Dev. 1996 Nov 1;10(21):2684-95.
PMID 8946910
 
Pharmacologic inactivation of kinase suppressor of ras-1 abrogates Ras-mediated pancreatic cancer.
Xing HR, Cordon-Cardo C, Deng X, Tong W, Campodonico L, Fuks Z, Kolesnick R.
Nat Med. 2003 Oct;9(10):1266-8. Epub 2003 Sep 7.
PMID 12960962
 
Kinase suppressor of Ras-1 protects intestinal epithelium from cytokine-mediated apoptosis during inflammation.
Yan F, John SK, Wilson G, Jones DS, Washington MK, Polk DB.
J Clin Invest. 2004 Nov;114(9):1272-80.
PMID 15520859
 

Citation

This paper should be referenced as such :
Fernandez, M ; Lewis, R
KSR1 (kinase suppressor of ras 1)
Atlas Genet Cytogenet Oncol Haematol. 2011;15(9):721-723.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/KSR1ID41107ch17q11.html


External links

Nomenclature
HGNC (Hugo)KSR1   6465
Cards
AtlasKSR1ID41107ch17q11
Entrez_Gene (NCBI)KSR1  8844  kinase suppressor of ras 1
AliasesKSR; RSU2
GeneCards (Weizmann)KSR1
Ensembl hg19 (Hinxton)ENSG00000141068 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000141068 [Gene_View]  chr17:27472010-27623692 [Contig_View]  KSR1 [Vega]
ICGC DataPortalENSG00000141068
TCGA cBioPortalKSR1
AceView (NCBI)KSR1
Genatlas (Paris)KSR1
WikiGenes8844
SOURCE (Princeton)KSR1
Genetics Home Reference (NIH)KSR1
Genomic and cartography
GoldenPath hg38 (UCSC)KSR1  -     chr17:27472010-27623692 +  17q11.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)KSR1  -     17q11.2   [Description]    (hg19-Feb_2009)
EnsemblKSR1 - 17q11.2 [CytoView hg19]  KSR1 - 17q11.2 [CytoView hg38]
Mapping of homologs : NCBIKSR1 [Mapview hg19]  KSR1 [Mapview hg38]
OMIM601132   
Gene and transcription
Genbank (Entrez)AK095721 AK124344 AK130719 BC035488 BC037586
RefSeq transcript (Entrez)NM_014238
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)KSR1
Cluster EST : UnigeneHs.133534 [ NCBI ]
CGAP (NCI)Hs.133534
Alternative Splicing GalleryENSG00000141068
Gene ExpressionKSR1 [ NCBI-GEO ]   KSR1 [ EBI - ARRAY_EXPRESS ]   KSR1 [ SEEK ]   KSR1 [ MEM ]
Gene Expression Viewer (FireBrowse)KSR1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)8844
GTEX Portal (Tissue expression)KSR1
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ8IVT5   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ8IVT5  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ8IVT5
Splice isoforms : SwissVarQ8IVT5
PhosPhoSitePlusQ8IVT5
Domaine pattern : Prosite (Expaxy)PROTEIN_KINASE_DOM (PS50011)    PROTEIN_KINASE_ST (PS00108)    ZF_DAG_PE_1 (PS00479)    ZF_DAG_PE_2 (PS50081)   
Domains : Interpro (EBI)Kinase-like_dom    KSR_SAM-like_dom    PE/DAG-bd    Prot_kinase_dom    Ser-Thr/Tyr_kinase_cat_dom    Ser/Thr_kinase_AS   
Domain families : Pfam (Sanger)KSR1-SAM (PF13543)    Pkinase_Tyr (PF07714)   
Domain families : Pfam (NCBI)pfam13543    pfam07714   
Domain families : Smart (EMBL)C1 (SM00109)  S_TKc (SM00220)  
Conserved Domain (NCBI)KSR1
DMDM Disease mutations8844
Blocks (Seattle)KSR1
SuperfamilyQ8IVT5
Human Protein AtlasENSG00000141068
Peptide AtlasQ8IVT5
IPIIPI01015914   IPI00217124   IPI01018676   IPI00013384   IPI00747688   IPI01026015   
Protein Interaction databases
DIP (DOE-UCLA)Q8IVT5
IntAct (EBI)Q8IVT5
FunCoupENSG00000141068
BioGRIDKSR1
STRING (EMBL)KSR1
ZODIACKSR1
Ontologies - Pathways
QuickGOQ8IVT5
Ontology : AmiGOMAPK cascade  protein kinase activity  protein kinase activity  signal transducer activity  MAP-kinase scaffold activity  protein binding  ATP binding  endoplasmic reticulum  endoplasmic reticulum membrane  cytosol  protein phosphorylation  Ras protein signal transduction  Ras protein signal transduction  Ras protein signal transduction  protein C-terminus binding  membrane  cAMP-mediated signaling  ruffle membrane  protein complex  positive regulation of MAPK cascade  positive regulation of MAPK cascade  metal ion binding  
Ontology : EGO-EBIMAPK cascade  protein kinase activity  protein kinase activity  signal transducer activity  MAP-kinase scaffold activity  protein binding  ATP binding  endoplasmic reticulum  endoplasmic reticulum membrane  cytosol  protein phosphorylation  Ras protein signal transduction  Ras protein signal transduction  Ras protein signal transduction  protein C-terminus binding  membrane  cAMP-mediated signaling  ruffle membrane  protein complex  positive regulation of MAPK cascade  positive regulation of MAPK cascade  metal ion binding  
Pathways : KEGGRas signaling pathway    Tuberculosis   
REACTOMEQ8IVT5 [protein]
REACTOME PathwaysR-HSA-6802955 [pathway]   
NDEx NetworkKSR1
Atlas of Cancer Signalling NetworkKSR1
Wikipedia pathwaysKSR1
Orthology - Evolution
OrthoDB8844
GeneTree (enSembl)ENSG00000141068
Phylogenetic Trees/Animal Genes : TreeFamKSR1
HOVERGENQ8IVT5
HOGENOMQ8IVT5
Homologs : HomoloGeneKSR1
Homology/Alignments : Family Browser (UCSC)KSR1
Gene fusions - Rearrangements
Fusion : MitelmanAGPAT3/KSR1 [21q22.3/17q11.1]  [t(17;21)(q11;q22)]  
Fusion : MitelmanCDR2L/KSR1 [17q25.1/17q11.1]  [t(17;17)(q11;q25)]  
Fusion : MitelmanCHD9/KSR1 [16q12.2/17q11.1]  [t(16;17)(q12;q11)]  
Fusion : MitelmanCYTH1/KSR1 [17q25.3/17q11.1]  [t(17;17)(q11;q25)]  
Fusion : MitelmanKSR1/EFCAB5 [17q11.1/17q11.2]  [t(17;17)(q11;q11)]  
Fusion : MitelmanKSR1/MSI2 [17q11.1/17q22]  [t(17;17)(q11;q22)]  
Fusion : MitelmanKSR1/PIPOX [17q11.1/17q11.2]  [t(17;17)(q11;q11)]  
Fusion : MitelmanKSR1/TENM1 [17q11.1/Xq25]  [t(X;17)(q25;q11)]  
Fusion : MitelmanMKS1/KSR1 [17q22/17q11.1]  [t(17;17)(q11;q22)]  
Fusion: TCGAAGPAT3 21q22.3 KSR1 17q11.1 BRCA
Fusion: TCGACDR2L 17q25.1 KSR1 17q11.1 LUSC
Fusion: TCGACHD9 16q12.2 KSR1 17q11.1 BRCA
Fusion: TCGACYTH1 17q25.3 KSR1 17q11.1 LUAD
Fusion: TCGAKSR1 17q11.1 EFCAB5 17q11.2 LUAD
Fusion: TCGAKSR1 17q11.1 MSI2 17q22 BRCA
Fusion: TCGAKSR1 17q11.1 ODZ1 LAML
Fusion: TCGAKSR1 17q11.1 PIPOX 17q11.2 BRCA
Fusion: TCGAMKS1 17q22 KSR1 17q11.1 BRCA
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerKSR1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)KSR1
dbVarKSR1
ClinVarKSR1
1000_GenomesKSR1 
Exome Variant ServerKSR1
ExAC (Exome Aggregation Consortium)KSR1 (select the gene name)
Genetic variants : HAPMAP8844
Genomic Variants (DGV)KSR1 [DGVbeta]
DECIPHERKSR1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisKSR1 
Mutations
ICGC Data PortalKSR1 
TCGA Data PortalKSR1 
Broad Tumor PortalKSR1
OASIS PortalKSR1 [ Somatic mutations - Copy number]
Mutations and Diseases : HGMDKSR1
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 KSR1
DgiDB (Drug Gene Interaction Database)KSR1
DoCM (Curated mutations)KSR1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)KSR1 (select a term)
intoGenKSR1
NCG5 (London)KSR1
Cancer3DKSR1(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM601132   
Orphanet
MedgenKSR1
Genetic Testing Registry KSR1
NextProtQ8IVT5 [Medical]
TSGene8844
GENETestsKSR1
Target ValidationKSR1
Huge Navigator KSR1 [HugePedia]
snp3D : Map Gene to Disease8844
BioCentury BCIQKSR1
ClinGenKSR1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD8844
Chemical/Pharm GKB GenePA30254
Clinical trialKSR1
Miscellaneous
canSAR (ICR)KSR1 (select the gene name)
Probes
Litterature
PubMed53 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineKSR1
EVEXKSR1
GoPubMedKSR1
iHOPKSR1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Tue Aug 1 17:29:36 CEST 2017

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