ROS1 (ROS proto-oncogene 1 , receptor tyrosine kinase)

2014-01-01   Samuel J Klempner  , Sai-Hong Ou  

University of California Irvine Medical Center, Orange, CA. sklempne@uci.edu; siou@uci.edu

Identity

HGNC
ROS1
LOCATION
6q22.1
LOCUSID
6098
ALIAS
MCF3,ROS,c-ros-1
FUSION GENES
Show Gene Fusions

Abstract

ROS1 is proto-oncogene encoding a type I integral membrane protein with receptor tyrosine kinase (RTK) activity. ROS1 is a member of the insulin receptor family and is involved in downstream signalling processes involved in cell growth and differentiation.

DNA/RNA

Description

The ROS1 gene is highly conserved from drosophila through zebrafish, rat, cow, rhesus, and homo sapiens. Refseq NM_002944.

Proteins

Expression

ROS1 expression is involved in regionalization of the proximal epididymal epithelium. Expression levels have been highest in liver, platelelts, T-cells and monocytes, but is found across nearly all cell types.

Localisation

ROS1 is localized to the cell plasma membrane and contains both extracellular and intracellular domains.

Function

ROS1 functions as an orphan receptor tyrosine kinase with an unestablished ligand. ROS1 directly interacts via an SH2 1 domain with PTPN6 which drives ROS1 dephosphorylation (Charest et al., 2006). ROS1 has also been suggested to interact with PTPN11 leading to PI3K/mTOR signaling, and to mediate phosphorylation of VAV3 (Charest et al., 2006). The ligand for wild type ROS1 is unknown and the normal function remains unclear despite the above associations.

Homology

ROS1 shares significant homology with other members of the insulin growth factor receptor family, and the gene is highly conserved back through drosophila melanogaster.

Mutations

Germinal

None established.

Somatic

The intrachromosomal del(6)(q21q22) deletion has been identified in glioblastoma multiforme and leads to the formation of a constitutive active GOPC-ROS1 protein (Charest et al., 2003). In non-small cell lung cancer (NSCLC) the SLC34A2-ROS1 chimeric protein also holds kinase activity. A CD74-ROS1 chimeric protein has also been identified in NSCLC (Awad et al., 2013).

Implicated in

Entity name
Non-small cell lung cancer, renal oncocytoma, gastric cancer, glioblastoma multiforme, cholangiocarcinoma colorectal cancer.
Note
There has been a rapidly expanding appreciation of ROS1 fusion proteins in the tumorigenesis of multiple malignancies as discussed below (Charest et. al., 2003, Gu et al., 2011, Rimkunas et al., 2012, Takeuchi et al.,2012, Awad et al., 2013, Lee et al., 2013).
Disease
ROS1 rearrangements occur in <2% of NSCLC and are enriched for in adenocarcinoma and young never smokers (Bergethon et al., 2012).
Prognosis
To date ROS1 has not been clearly implicated as an independent prognostic variable. ROS1 rearrangements may predict sensitivity to the ALK-inhibitor Crizotinib in NSCLC. Small molecule inhibitor screens have also identified foretinib as a potent inhibitor of multiple ROS1 fusion proteins. Additionaly, ROS1 mutation has been observed as a acquired resistance mechanism to crizotinib. Davare and colleagues have shown that foretinib is capable of inhibiting the G2032R ROS1 mutant which is resistant to crizotinib (Davare et al., 2013).
Cytogenetics
ROS1 rearrangements have been documented with the following fusion partners; CCDC6, CD74, CEP85L, also called C6orf204, CLTC, EZR, GOPC, KDELR2, LRIG3, SDC4, SLC34A2, and TPM3.
Translocations and fusion proteins: t(1;6)(q21;q22) TPM3/ROS1; t(4;6)(p15;q22) SLC34A2/ROS1; t(5;6)(q33;q22) CD74/ROS1; t(6;6)(q22;q22) GOPC/ROS1; t(6;6)(q22;q22) CEP85L/ROS1; t(6;6)(q22;q25) EZR/ROS1; t(6;7)(q22;p22) KDELR2/ROS1; t(6;10)(q22;q21) CCDC6/ROS1; t(6;12)(q22;q14) LRIG3/ROS1; t(6;17)(q22;q23)CLTC/ROS1; t(6;20)(q22;q12) SDC4/ROS1 (Charest et. Al., 2003, Gu et al., 2011, Rimkunas et al., 2012, Takeuchi et al., 2012, Awad et al., 2013, Lee et al., 2013, Mitelman et al., 2015). Within NSCLC ROS1 rearrangements are non-overlapping with EGFR, KRAS, and ALK genomic alterations (Davies et al., 2012, Awad et al., 2013, Go et al., 2013).

Breakpoints

Atlas Image

Note

Within the COSMIC database ROS1 chromosomal rearrangements have been documented with the following fusion partners ; CD74, EZR, GOPC, SDC4, TPM3, SLC34A2, and LRIG3 (COSMIC, accessed 12/2013).

Article Bibliography

Pubmed IDLast YearTitleAuthors
242967582014ROS1 and ALK fusions in colorectal cancer, with evidence of intratumoral heterogeneity for molecular drivers.Aisner DL et al
237249142013Acquired resistance to crizotinib from a mutation in CD74-ROS1.Awad MM et al
222157482012ROS1 rearrangements define a unique molecular class of lung cancers.Bergethon K et al
126610062003Fusion of FIG to the receptor tyrosine kinase ROS in a glioblastoma with an interstitial del(6)(q21q21).Charest A et al
168853442006ROS fusion tyrosine kinase activates a SH2 domain-containing phosphatase-2/phosphatidylinositol 3-kinase/mammalian target of rapamycin signaling axis to form glioblastoma in mice.Charest A et al
230702422012Targeting ROS1 with anaplastic lymphoma kinase inhibitors: a promising therapeutic strategy for a newly defined molecular subset of non-small-cell lung cancer.Chin LP et al
234151112013Aberrant activation of ROS1 represents a new molecular defect in chronic myelomonocytic leukemia.Cilloni D et al
242185892013Foretinib is a potent inhibitor of oncogenic ROS1 fusion proteins.Davare MA et al
237192672013Molecular pathways: ROS1 fusion proteins in cancer.Davies KD et al
229190032012Identifying and targeting ROS1 gene fusions in non-small cell lung cancer.Davies KD et al
238140432013Novel targets in non-small cell lung cancer: ROS1 and RET fusions.Gainor JF et al
241287152013Clinicopathologic analysis of ROS1-rearranged non-small-cell lung cancer and proposal of a diagnostic algorithm.Go H et al
212535782011Survey of tyrosine kinase signaling reveals ROS kinase fusions in human cholangiocarcinoma.Gu TL et al
234005462013Identification of ROS1 rearrangement in gastric adenocarcinoma.Lee J et al
225006822012ROS1 as a 'druggable' receptor tyrosine kinase: lessons learned from inhibiting the ALK pathway.Ou SH et al
226615372012Analysis of receptor tyrosine kinase ROS1-positive tumors in non-small cell lung cancer: identification of a FIG-ROS1 fusion.Rimkunas VM et al
223276232012RET, ROS1 and ALK fusions in lung cancer.Takeuchi K et al
226172452012Preclinical rationale for use of the clinically available multitargeted tyrosine kinase inhibitor crizotinib in ROS1-translocated lung cancer.Yasuda H et al

Other Information

Locus ID:

NCBI: 6098
MIM: 165020
HGNC: 10261
Ensembl: ENSG00000047936

Variants:

dbSNP: 6098
ClinVar: 6098
TCGA: ENSG00000047936
COSMIC: ROS1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000047936ENST00000368507Q5H8Y1
ENSG00000047936ENST00000368508P08922
ENSG00000047936ENST00000403284H0Y3T9

Expression (GTEx)

0
5
10
15
Adipose - Subcutaneous
Adipose - Visceral
Adrenal Gland
Artery - Aorta
Artery - Tibial
Bladder
Brain - Amygdala
Brain - Anterior cingulate cortex
Brain - Caudate
Brain - Cerebellar Hemisphere
Brain - Cerebellum
Brain - Cortex
Brain - Frontal Cortex
Brain - Hippocampus
Brain - Hypothalamus
Brain - Nucleus accumbens
Brain - Putamen
Brain - Spinal cord
Brain - Substantia nigra
Breast - Mammary Tissue
Cells - Cultured fibroblasts
Cells - EBV - transformed lymphocytes
Cervix - Ectocervix
Cervix - Endocervix
Colon - Sigmoid
Colon - Transverse
Esophagus - Gastroesophageal Junction
Esophagus - Mucosa
Esophagus - Muscularis
Fallopian Tube
Heart - Atrial Appendage
Heart - Left Ventricle
Kidney - Cortex
Kidney - Medulla
Liver
Lung
Minor Salivary Gland
Muscle - Skeletal
Nerve - Tibial
Ovary
Pancreas
Pituitary
Prostate
Skin - Not Sun Exposed
Skin - Sun Exposed
Small Intestine - Terminal Ileum
Spleen
Stomach
Testis
Thyroid
Uterus
Vagina
Whole Blood

Protein levels (Protein atlas)

Not detected
Low
Medium
High
N/A

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA165946122crizotinibChemicalLabelAnnotationassociated
PA166182743lorlatinibChemicalLabelAnnotationassociated
PA166190161entrectinibChemicalLabelAnnotationassociated

References

Pubmed IDYearTitleCitations
381486352024CD74-ROS1 L2026M mutant enhances autophagy through the MEK/ERK pathway to promote invasion, metastasis and crizotinib resistance in non-small cell lung cancer cells.1
384684432024RB1 loss induces quiescent state through downregulation of RAS signaling in mammary epithelial cells.1
381486352024CD74-ROS1 L2026M mutant enhances autophagy through the MEK/ERK pathway to promote invasion, metastasis and crizotinib resistance in non-small cell lung cancer cells.1
384684432024RB1 loss induces quiescent state through downregulation of RAS signaling in mammary epithelial cells.1
368046222023ROS1 as a possible prognostic biomarker of cervical adenocarcinoma: An exploratory analysis with next-generation sequencing.0
372373842023"Evaluation of ROS1 expression and rearrangements in a large cohort of early-stage lung cancer".1
375112552023Therapeutical Options in ROS1-Rearranged Advanced Non Small Cell Lung Cancer.0
375795772023Clinicopathologic and molecular characteristics of small-scale ROS1-mutant non-small cell lung cancer (NSCLC) patients.0
375878722023Discovery of oncogenic ROS1 missense mutations with sensitivity to tyrosine kinase inhibitors.3
378567632023Inflammatory Myofibroblastic Tumor With ROS1 Gene Fusions in Children and Young Adolescents.1
368046222023ROS1 as a possible prognostic biomarker of cervical adenocarcinoma: An exploratory analysis with next-generation sequencing.0
372373842023"Evaluation of ROS1 expression and rearrangements in a large cohort of early-stage lung cancer".1
375112552023Therapeutical Options in ROS1-Rearranged Advanced Non Small Cell Lung Cancer.0
375795772023Clinicopathologic and molecular characteristics of small-scale ROS1-mutant non-small cell lung cancer (NSCLC) patients.0
375878722023Discovery of oncogenic ROS1 missense mutations with sensitivity to tyrosine kinase inhibitors.3

Citation

Samuel J Klempner ; Sai-Hong Ou

ROS1 (ROS proto-oncogene 1 , receptor tyrosine kinase)

Atlas Genet Cytogenet Oncol Haematol. 2014-01-01

Online version: http://atlasgeneticsoncology.org/gene/42144/ros1-(ros-proto-oncogene-1-receptor-tyrosine-kinase)