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This proto-oncogene, highly-expressed in a variety of tumor cell lines, belongs to the sevenless subfamily of tyrosine kinase insulin receptor genes. The protein encoded by this gene is a type I integral membrane protein with tyrosine kinase activity. The protein may function as a growth or differentiation factor receptor. [provided by RefSeq, Jul 2008]
ROS1 is a receptor tyrosine kinase that is frequently involved in genetic rearrangement in a variety of human cancers (e.g. NSCLC, gastric cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, angiosarcoma...). The resulting fusion protein harbors the constitutively active ROS1 kinase domain and drives cellular proliferation (Davies et. al.). In NSCLC about 1% harbor a ROS1 rearrangement. These patients are predominantely female and have a lower T-stage (Warth et. al.). Treatment with crizotinib leads to a reported objective response rate of appr. 70% and a median duration of response of 18 months (Shaw et. al.). Resistance mechanisms to crizotinib have been described and involve mutations in the kinase domain. More selective inhibitors of ROS1 might overcome this resistance (Davare et. al.).
ROS1 (ROS Proto-Oncogene 1, Receptor Tyrosine Kinase) is a Protein Coding gene. Diseases associated with ROS1 include Lung Cancer Susceptibility 3 and Lung Large Cell Carcinoma. Among its related pathways are Activation of cAMP-Dependent PKA and Actin Nucleation by ARP-WASP Complex. Gene Ontology (GO) annotations related to this gene include transferase activity, transferring phosphorus-containing groups and protein tyrosine kinase activity. An important paralog of this gene is INSR.
GeneHancer (GH) Identifier | GH Type | GH Score |
GH Sources | Gene Association Score | Total Score | TSS distance (kb) | Number of Genes Away | Size (kb) | Transcription Factor Binding Sites |
Gene Targets |
---|---|---|---|---|---|---|---|---|---|---|
GH06J117439 | Promoter/Enhancer | 1.6 | EPDnew Ensembl ENCODE dbSUPER | 605.4 | -15.6 | -15632 | 3.8 | CEBPG GATAD2A ZNF629 TFE3 SOX13 NFKBIZ RCOR2 RXRB IRF2 REST | ROS1 DCBLD1 NUS1 ENSG00000226181 lnc-DCBLD1-2 ENSG00000282218 | |
GH06J117446 | Promoter/Enhancer | 1.4 | EPDnew Ensembl ENCODE dbSUPER | 600.4 | -23.4 | -23431 | 5.8 | CTCF PRDM10 REST RAD21 TRIM22 CEBPA CEBPB SP1 JUND ATF3 | ROS1 DCBLD1 SLC35F1 CALHM6 ENSG00000226181 lnc-DCBLD1-2 ENSG00000282218 | |
GH06J117425 | Promoter/Enhancer | 0.9 | EPDnew Ensembl ENCODE | 605.6 | +0.1 | 144 | 1.8 | HLF | ROS1 DCBLD1 ENSG00000226181 HSALNG0053054 ENSG00000282218 VGLL2 | |
GH06J117344 | Promoter | 0.4 | EPDnew | 600.2 | +82.0 | 82012 | 0.1 | RFX1 | ROS1 piR-57229 piR-47162-147 VGLL2 ENSG00000282218 | |
GH06J117418 | Promoter | 0.3 | EPDnew | 600.4 | +7.5 | 7482 | 0.1 | ROS1 HSALNG0053054 VGLL2 ENSG00000282218 |
GO ID | Qualified GO term | Evidence | PubMed IDs |
---|---|---|---|
GO:0000166 | nucleotide binding | IEA | -- |
GO:0004672 | protein kinase activity | IEA | -- |
GO:0004713 | protein tyrosine kinase activity | IEA,IDA | 16885344 |
GO:0004714 | transmembrane receptor protein tyrosine kinase activity | IEA,IBA | 21873635 |
GO:0005515 | protein binding | IEA,IPI | 17416557 |
GO ID | Qualified GO term | Evidence | PubMed IDs |
---|---|---|---|
GO:0005886 | plasma membrane | IEA | -- |
GO:0005887 | integral component of plasma membrane | IBA | 21873635 |
GO:0009986 | cell surface | IEA | -- |
GO:0016020 | membrane | IEA,TAS | 3785223 |
GO:0016021 | integral component of membrane | IEA | -- |
SuperPathway | Contained pathways | ||
---|---|---|---|
1 | GPCR Pathway |
Paxillin Interactions
.73
Ras Pathway
.73
GPCR Pathway
.62
Pancreatic Adenocarcinoma
.59
|
Breast Cancer Regulation by Stathmin1
.58
NFAT in Immune Response
.58
Estrogen Pathway
.55
P2Y Receptor Signaling
.38
|
2 | ERK Signaling |
ERK Signaling
.61
Rho Family GTPases
.61
MAPK Signaling
.58
|
Molecular Mechanisms of Cancer
.51
ILK Signaling
.49
|
3 | Nanog in Mammalian ESC Pluripotency |
GSK3 Signaling
.62
Nanog in Mammalian ESC Pluripotency
.62
|
14-3-3 Induced Intracellular Signaling
.59
eNOS Signaling
.48
|
4 | Actin Nucleation by ARP-WASP Complex |
Actin Nucleation and Branching
.66
Actin Nucleation by ARP-WASP Complex
.66
|
CDC42 Pathway
.41
|
5 | Activation of cAMP-Dependent PKA |
Activation of cAMP-Dependent PKA
.77
|
Activation of PKA through GPCR
.71
|
GO ID | Qualified GO term | Evidence | PubMed IDs |
---|---|---|---|
GO:0001558 | regulation of cell growth | IDA | 16885344 |
GO:0002066 | columnar/cuboidal epithelial cell development | IEA,ISS | -- |
GO:0006468 | protein phosphorylation | IEA,IDA | 16885344 |
GO:0007169 | transmembrane receptor protein tyrosine kinase signaling pathway | IEA,IBA | 21873635 |
GO:0007275 | multicellular organism development | IBA | 21873635 |
Name | Status | Disease Links | Group | Role | Mechanism of Action | Clinical Trials |
---|---|---|---|---|---|---|
Entrectinib | Approved, Investigational | Pharma | Target, inhibitor | Orally active inhibitor of ALK kinase | 15 | |
Crizotinib | Approved | Pharma | Inhibition, Biomarker, inhibitor | C-MET/ALK inhibitor,potent and ATP-competitve, Potent c-MET/ALK inhibitor, cMET Inhibitors, Kinase Inhibitors, Anaplastic lymphoma kinase (ALK) inhibitor | 140 | |
Tyrosine | Approved, Investigational | Nutra | 1044 | |||
fostamatinib | Approved, Investigational | Pharma | Target, inhibitor | Kinase Inhibitors | 0 | |
lorlatinib | Approved, Investigational | Pharma | 0 |
Name | Synonyms | Role | CAS Number | PubChem IDs | PubMed IDs | |
---|---|---|---|---|---|---|
ADP |
|
Agonist, Full agonist, Partial agonist, Gating inhibitor, Antagonist | 58-64-0 |
|
Compound | Action | Cas Number |
---|---|---|
Dovitinib (TKI-258, CHIR-258) | Multitargeted RTK inhibitor | 405169-16-6 |
This gene was present in the common ancestor of animals.
Organism | Taxonomy | Gene | Similarity | Type | Details |
---|---|---|---|---|---|
Chimpanzee (Pan troglodytes) |
Mammalia | ROS1 30 31 |
|
OneToOne | |
Cow (Bos Taurus) |
Mammalia | ROS1 30 31 |
|
OneToOne | |
Dog (Canis familiaris) |
Mammalia | ROS1 30 31 |
|
OneToOne | |
Mouse (Mus musculus) |
Mammalia | Ros1 30 17 31 |
|
OneToOne | |
Rat (Rattus norvegicus) |
Mammalia | Ros1 30 |
|
||
Oppossum (Monodelphis domestica) |
Mammalia | ROS1 31 |
|
OneToOne | |
Platypus (Ornithorhynchus anatinus) |
Mammalia | ROS1 31 |
|
OneToOne | |
Chicken (Gallus gallus) |
Aves | ROS1 30 31 |
|
OneToOne | |
Lizard (Anolis carolinensis) |
Reptilia | -- 31 |
|
ManyToMany | |
Tropical Clawed Frog (Silurana tropicalis) |
Amphibia | ros1 30 |
|
||
Zebrafish (Danio rerio) |
Actinopterygii | ros1 30 31 |
|
OneToOne | |
Fruit Fly (Drosophila melanogaster) |
Insecta | sev 30 31 32 |
|
OneToOne | |
African malaria mosquito (Anopheles gambiae) |
Insecta | AgaP_AGAP000015 30 |
|
||
Worm (Caenorhabditis elegans) |
Secernentea | T21G5.1 32 |
|
|
|
R151.4 32 |
|
|
|||
ZK593.9 32 |
|
|
|||
ddr-1 31 |
|
ManyToMany |
SNP ID | Clinical significance and condition | Chr 06 pos | Variation | AA Info | Type |
---|---|---|---|---|---|
708343 | Benign: not provided | 117,397,024(-) | G/A | MISSENSE_VARIANT | |
708375 | Likely Benign: not provided | 117,356,626(-) | T/C | INTRON_VARIANT | |
709394 | Benign: not provided | 117,310,138(-) | C/T | MISSENSE_VARIANT | |
710627 | Likely Benign: not provided | 117,383,402(-) | G/T | MISSENSE_VARIANT | |
712067 | Likely Benign: not provided | 117,387,836(-) | G/A | MISSENSE_VARIANT |
Variant ID | Type | Subtype | PubMed ID |
---|---|---|---|
dgv6141n100 | CNV | gain | 25217958 |
esv2635247 | CNV | deletion | 19546169 |
esv2759465 | CNV | loss | 17122850 |
esv2763593 | CNV | gain | 21179565 |
esv3303146 | CNV | mobile element insertion | 20981092 |
esv3383830 | CNV | insertion | 20981092 |
esv3610491 | CNV | loss | 21293372 |
nsv478464 | CNV | novel sequence insertion | 20440878 |
nsv510048 | OTHER | sequence alteration | 20534489 |
nsv526934 | CNV | loss | 19592680 |
nsv830785 | CNV | gain | 17160897 |
Disorder | Aliases | PubMed IDs |
---|---|---|
lung cancer susceptibility 3 |
|
|
lung large cell carcinoma |
|
|
large cell carcinoma |
|
|
adenocarcinoma |
|
|
sarcoma |
|
|