OMIM search
Folate binding protein: FOLATE RECEPTOR 1, ADULT; FOLR1
Function: The folate receptor 1, adult, has a high affinity for folic acid and some of its derivatives. There exist both a membrane-bound form, which has been shown to mediate the transport of folate to cells, and a soluble form, whose function has not been identified yet. (OMIM)
Have been found in kidney, placenta, serum, milk, and in several cell lines
Folate
Folic acid and folate (the anion form) are forms of the water-soluble Vitamin B9.
Folate is needed to synthesize DNA bases and thus is important for DNA synthesis and cell division. In the form of tetrahydrofolate (THF) compounds, folate derivatives are needed in single-carbon-transfer reactions. (Wikipedia)
Folate, Ovarian cancers and vaccine
Folate binding protein is overexpressed in more than 90% of ovarian cancers. FBP peptides cam be recognized by freshly isolated Tumor-associated lymphocytes from ovarian cancer patients. These peptides may be used in a peptide-based vaccine for ovarian cancers and other epithelial tumors. (PMID: 9869522)
hnRNP K and cancer
Heterogeneous ribonucleoprotein K (hnRNP K) is a member of the hnRNP protein family. These proteins have different cellular functions, for instance transcription, mRNA shuttling, RNA editing and translation. HnRNP is thought to play a role in tumorigenisis as well, for example by positively influencing transcription of c-myc. (PMID: 16953238)
Connection between hnRNP E1, folate receptor and Lamin A/C
The translational upregulation of folate receptors is mediated via hnRNP E1 interactions. (PMID: 14722620). The hnRNP protein interacts with Lamin A/C (PMID: 16248985).
hnRNP E1 are also connected with lamin A/C, which is suggested in the article “Novel progerin-interactive partner proteins hnRNP E1, EGF, Mel 18, and UBC9 interact with lamin A/C”.
B)
Periostin and Breast cancer
It is a secreted adhesion protein, which seems to take part in angiogenesis of epithelial tumors when overexpressed. It shows abnormal nuclear localization in some Breast cancers. (PMID: 17938160).
Gillan, L.; Matei, D.; Fishman, D. A.; Gerbin, C. S.; Karlan, B. Y.; Chang, D. D. :
Periostin secreted by epithelial ovarian carcinoma is a ligand for alpha-V-beta-3 and alpha-V-beta-5 integrins and promotes cell motility. Cancer Res. 62: 5358-5364, 2002.
Alpha 6 integrin
The alpha 6 integrin subunit functions as laminin receptor and binds to the long arm of laminin. (OMIM). Integrins are integral cell-surface proteins composed of an alpha chain and a beta chain. (EntrezGene).
LAMx Laminins, a family of extracellular matrix glycoproteins, are the major noncollagenous constituent of basement membranes. They have been implicated in a wide variety of biological processes including cell adhesion, differentiation, migration, signaling, neurite outgrowth and metastasis.
Connection between Periostin, Alpha 6 integrin and Laminin
Alpha 6 integrin binds to the long arm of laminin, it functions as a laminin receptor. (OMIM)
?Epithelial to Mesenchymal transition might be important for the development of invasive tumors and metastasis.
C)
Elongation factor 1 alpha
The alpha subunit of elongation factor-1 (EEF1A) is involved in the binding of aminoacyl-tRNAs to 80S ribosomes while hydrolyzing GTP. (OMIM)
Putative ovarian oncogene
Nobukuni Y, Kohno K, Miyagawa K.
Alternative names:
ELONGATION FACTOR 1, ALPHA-1
ELONGATION FACTOR 1, ALPHA; EF1A; EEF1A
CERVICAL CANCER SUPPRESSOR 3, INCLUDED; CCS3, INCLUDED
DPH1
DPH1 is one of several enzymes that are involved in the synthesis of diphtamide, which is a posttranslationally modified histidine, that is only found in translation elongation factor 2. This modification is also a target for the inactivation of EEF2 by diphtheria toxin and Pseudomonas exotoxin. Therefore, a mutation in DPH1 migth give resistance to those toxins.
DPH1 is 1 of several enzymes involved in synthesis of diphthamide in EEF2 (Liu et al., 2004 [PubMed 15485916]).[supplied by OMIM]
Is deleted in 80% of all ovarian epithelial malignancies
The chromosomal region where DPH1 is located is the p-terminal region of chromosome 17. It also contains a breast cancer-related regulator (BCPR) of TP53, which is a tumor suppressor gene frequently deleted in breast cancer cells.
Gene locus associated with three disorders: Bleeding disorder due to P2RX1 defect, Subcortical laminar heterotopia, and Retinitis pigmentosa-13. Also, OVCA1 and OVCA2, that map to 17p13.3 contributes to ovarian tumorigenesis and should be considered candidate tumor suppressor genes.
Relationship between DPH1 and DPH2
With the help of immunoprecipitation analysis it was shown that yeast and mouse Dph1 and Dph2 interacted. This suggested, that these enzymes might function as a dimer or multimer in the biosynthesis of diphthamide. (OMIM)
OVCA1
OVCA1 appears to be the homolog of yeast DPH2, which participates in the first biosynthetic step of diphthamide.
D)
BRCA1, BRCA2 and PALB2
The BRCA1 and BRCA2 genes are involved in maintenance of genome stability. Inherited mutations in those genes confer a high risk of developing breast cancer or ovarian cancer. BRCA1 and BRCA2 are considered to be tumor suppressor genes. (EntrezGene)
PALB2 colocalizes with BRCA2 in nuclear foci, promotes its localization and stability in nuclear structures, and enables its recombinational repair and checkpoint functions. It could be so that BRCA2 is involved in ovarian cancer, an article in PubMed says for instance that “Loss of five amino acids in BRCA2 is associated with ovarian cancer”. In many cases one has seen an up-regulation of the gene in people who have ovarian cancer.
A small proportion of breast cancer, in particular those cases arising at a young age, are due to the inheritance of dominant susceptibility genes conferring a high risk of the disease. The first of these genes to be confirmed was BRCA1, which is located on chromosome 17. BRCA1 is therefore mainly involved in breast cancer. BRCA1 may normally serve as a negative regulator of mammary epithelial cell growth and that function is compromised in breast cancer either by direct mutation or by alterations in gene expression.
As seen in many articles on PubMed, BRCA2 and BRCA1 are mentioned together in many contexts. What can be said is that BRCA2 is mainly involved in ovarian cancer and BRCA1 in breast cancer. Mutations in the BRCA1 gene account for most families with the hereditary breast-ovarian cancer syndrome.
That BRCA2 and PALB2 were associated with stable nuclear structures and were likely complexed in chromatin. Immunodepletion of BRCA2 codepleted much of PALB2, whereas immunodepletion of PALB2 codepleted nearly all BRCA2.
Aberrant promoter hypermethylation of PALB2 is more frequent than the reported level of PALB2 point mutations in breast tumors from BRCA1/2-negative families and is similar to the frequency of BRCA1 hypermethylation in inherited and sporadic breast and ovarian cancers. PMID: 18281473 [PubMed - indexed for MEDLINE]
PALB1 may also be involved in ovarian cancer. It co-localizes with and binds to BRCA2, and hypermethylation of the PLAB1 promoter has been shown to be present in some ovarian cancers. (PMID: 18281473).
No real evidence that PALB2 is involved in ovarian cancer, actually it seams to not be involved.
Swissprot search
Entry name FOLR1_HUMAN
Primary accession number P15328
What is the function of folate binding protein?
FUNCTION: Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate to the interior of cells.
Where is the protein found in the cell?
SUBCELLULAR LOCATION: Cell membrane; Secreted (Probable).
How is it kept
there? Lipid-anchor, GPI-anchor
Look at the feature viewer. What modifications are present on the protein and what does it
suggest about whether the protein is inside or outside of the cell.
Due to N-linked glycosylation probably outside the cell.
Entry name HNRPK_HUMAN
Primary accession number P61978
What modifications are found on
hnRNP K. MOD_RES 1 1 N-acetylmethionine.
MOD_RES 3 3 Phosphothreonine.
MOD_RES 36 36 Phosphoserine.
MOD_RES 116 116 Phosphoserine.
MOD_RES 214 214 Phosphoserine.
MOD_RES 216 216 Phosphoserine.
MOD_RES 284 284 Phosphoserine.
MOD_RES 296 296 Omega-N-methylated arginine.
MOD_RES 299 299 Omega-N-methylated arginine.
MOD_RES 379 379 Phosphoserine.
What proteins does hnRNP K interact with (click on protein-protein interaction
database). Interacts with Tyrosine-protein kinase HCK and QKI_HUMAN RNA-binding protein. HNPK, MYC, EGFR, RBM41, NPDC1, KHDRBS3, KHDRBS2, CNNM3, DIDO1, GRAP2, MATR3, MGC10433, RBM7, NCK2, SORBS3, RBMX, UBE2I, QKI, TOP1, PCBP1, GFI1B, HCK, GRB2
Does this fit with what you found yesterday?
Lamin A/C (LMNA) was not listed in the protein interaction table.
Neither the folate receptor nor Lamin A/C are mentioned in the interaction list.
Look at the pathways. Go back to
SwissProt and look at the Reactome link under mRNA processing. View by clicking on
Cytoscape.
Does this view help you?
Remarks:
· No.
· The Cytoscape view is heavily overloaded, but the otherwise a nice tool.
· Some students found it useful.
Can you find a connection between hnRNP E1, folate
receptor and Lamin A/C (look in the interaction lists). No
B. Look up the following genes in SwissProt: (1) Periostin; (2) Alpha 6 Integrin and (3) Laminin A
Where is periostin found in the cell? Extracellular matrix
Secreted
What modifications support this. PTM Glycoprotein (N-linked (GlcNAc...))
There are three positions for disulphide bonds given (by similarity) that support the extracellular location.
DISULFID 44 80 By similarity.
DISULFID 60 69 By similarity.
DISULFID 79 92 By similarity.
Is there any evidence for protein-protein interaction. No
Integrin alpha-6/beta-1 is a receptor for laminin on platelets. Integrin alpha-6/beta-4 is a receptor for laminin in epithelial cells and it plays a critical structural role in the hemidesmosome.
Where is alpha 6 integrin found in the cell? Membrane; Single-pass type I membrane protein.
What modifications
support this. N-linked (GlcNAc...)
Is there any evidence for protein-protein interaction. No
Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components.
Where is Laminin A found in the
cell? Secreted, extracellular space, extracellular matrix, basement membrane. Note=Major component.
What modifications support this. N-linked (GlcNAc...) High number of disulphide bonds (by similiarity), two interchain disulphide bonds (probable).
Is there any evidence for protein-protein interaction. No
Look under the gene ontology section. What is the laminin 1 complex? Laminins are composed of 3 non identical chains: laminin alpha, beta and gamma (formerly A, B1, and B2, respectively) and they form a cruciform structure consisting of 3 short arms, each formed by a different chain, and a long arm composed of all 3 chains.
Do a google search on this term.
Does the information help?
Remarks:
Yes
No
C. Look up the following genes in SwissProt: (1) Elongation factor 1 alpha, EF1 (2) Diphthamide
synthesis protein, DPH1 and (3) DHP2.
This protein promotes the GTP-dependent binding of aminoacyl-tRNA to the A-site of ribosomes during protein biosynthesis.
What post-translational modifications does EF1 have?
MOD_RES 29 29 Phosphotyrosine.
MOD_RES 36 36 N6,N6,N6-trimethyllysine (By similarity).
MOD_RES 55 55 N6,N6-dimethyllysine (By similarity).
MOD_RES 79 79 N6,N6,N6-trimethyllysine (By similarity).
MOD_RES 162 162 Phosphotyrosine.
MOD_RES 165 165 N6,N6-dimethyllysine (By similarity).
MOD_RES 318 318 N6,N6,N6-trimethyllysine; alternate (By similarity).
MOD_RES 318 318 N6-acetyllysine; alternate.
· What are the function of these modifications.
Post-translational modifications on EF1: phoshotyrosine, trimethyllysine, dimethyllysine and acetyllysine. Phosphorylation of proteins activates the protein. Methylation regulates the activation of the protein. Acetylation of a protein makes the break down of the protein more difficult.
· Look for protein-protein interactions.
76 protein interactions found, but not with DPH1 or DPH2.
· Does it interact with either of the DPH gene products.
No
· Look up Diphthamide synthesis protein. Does it interact with anything.
Breast cancer anti-estrogen resistance protein 3 are interacting with a few of the given proteins above, strange???
SUBUNIT: Interacts with DPH2 (By similarity). Interacts with RBM8A.
· Are there any important modifications known?
No modifications, just variants.
D. Look up PALB2 in SwissProt (partner and localiser of BRCA2)
· What modifications are known for PALB2?
PALB2
Key From To Length Description
CHAIN 1 1186 1186 Partner and localizer of BRCA2.
MOD_RES 59 59 Phosphoserine.
MOD_RES 64 64 Phosphoserine.
MOD_RES 157 157 Phosphoserine.
MOD_RES 376 376 Phosphoserine.
MOD_RES 660 660 Phosphoserine.
· Are these important in disease?
# DISEASE: Variations in PALB2 are associated with breast cancer susceptibility.
# DISEASE: Defects in PALB2 are the cause of Fanconi anemia complementation group N (FANCN) [MIM:610832]. FA [MIM:227650] is a genetically heterogeneous, autosomal recessive disorder characterized by progressive pancytopenia, a diverse assortment of congenital malformations, and a predisposition to the development of malignancies. At the cellular level it is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage), and defective DNA repair.
· What interactions are known.
SUBUNIT: Interacts with BRCA2.
One interaction found with ALB.
· What is ALB and where is it usually found. Is this an important partner?
# FUNCTION: Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloidal osmotic pressure of blood.
# SUBCELLULAR LOCATION: Secreted.
Not an important binding partner, since it binds to a lot of proteins with low specitity.
III
A. Look up the following genes in SwissProt: (1) Human Folate Binding Protein; (2) hnRNP K and
also E1 (heterogenous ribonucleoprotein E1) and (3) Lamin A/C.
Look up folate binding protein in SwissProt. Click on the link ProtoNet then follow the link to Go
to cluster. What can you find? Click on the folate binding cluster and then view Proteins of
Cluster. Wait. What is in this cluster.
No. ProtoNet Protein ID ID in Source Prosite ID's Name of protein Length Belongs to child Check protein for BLAST
1 P-57231 RBP_CHICK SW Riboflavin-binding protein precursor (RBP) 238
2 P-976417 Q9YGJ4 TR Riboflavin binding protein precursor 235
3 P-311454 Q9XSH1 TR Membrane-bound folate binding protein 249
4 P-317320 Q9XSH0 TR Secreted folate binding protein 252
5 P-284276 Q9VFM4 TR CG14359 protein 78
6 P-211249 Q9UCT2 TR Folate-binding PROTEIN=TUMOR-associated antigen (Fragment) 27
7 P-837680 Q9R223 TR Folate receptor alpha (Fragment) 42
8 P-852602 Q9R222 TR Folate receptor alpha 255
9 P-851949 Q9QUY0 TR Folate binding protein I (Fragment) 22