Cbl gene
Encyclopedia
Cbl is a mammalian gene encoding several proteins including E3 ubiquitin-protein ligase CBL involved in cell signalling and protein ubiquitination. Mutations to this gene have been implication in a number of human cancers, particularly acute myeloid leukaemia.
binding domain
, and that this was the oncogenic form as retroviruses carrying full-length c-Cbl did not induce tumour formation. The resultant transformed retrovirus was found to consistently induce a type of pre-B lymphoma, known as Casitas B-lineage lymphoma, in infected mice.
This domain structure and the tyrosine
and serine
-rich content of the protein product is typical of an "adaptor molecule" used in cell signalling pathways.
have been characterized, which all differ in their ability to function as adaptor proteins due to the differing lengths of their C-terminal UBA domains:
Interestingly, both c-Cbl and Cbl-b have orthologues
in D. melanogaster
(D-Cbl) and C. elegans
(Sli-1), hinting at a long evolutionary path for these proteins.
monomers to a protein, thereby targeting it for degradation. As this is a multi-step process, several different enzymes are involved, the final one being a member of the E3 family of ligase
s. Cbl functions as an E3 ligase, and therefore is able to catalyse the formation of a covalent bond between ubiquitin and Cbl's protein substrate - typically a receptor tyrosine kinase
. The RING-finger domain mediates this transfer, however like other E3 ligases of the RING type no intermediate covalent bond is formed between ubiquitin and the RING-finger domain. The stepwise attachment of ubiquitin to the substrate receptor tyrosine kinase can lead to its removal from the plasma membrane and subsequent trafficking to the lysosome
for degradation.
with:
Discovery
In 1989 a virally encoded portion of the chromosomal mouse Cbl gene was the first member of the Cbl family to be discovered and was named v-Cbl to distinguish it from normal mouse c-Cbl. The virus used in the experiment was a retrovirus known as Cas-Br-M, and was found to have excised approximately a third of the original c-Cbl gene from mice it was injected into. Sequencing revealed that the portion carried by the retrovirus encoded a tyrosine kinaseTyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
binding domain
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
, and that this was the oncogenic form as retroviruses carrying full-length c-Cbl did not induce tumour formation. The resultant transformed retrovirus was found to consistently induce a type of pre-B lymphoma, known as Casitas B-lineage lymphoma, in infected mice.
Structure
Full length c-Cbl has been found to consist of several regions encoding for functionally distinct protein domains:- N-terminal tyrosine kinase binding domainCbl TKB domainIn molecular biology, the Cbl TKB domain , also known as the phosphotyrosine binding domain is a conserved region found at the N-terminus of Cbl adaptor proteins...
(TKB domain): determines the protein which it can bind to - RING finger domainRING finger domainIn molecular biology, a RING finger domain is a protein structural domain of zinc finger type which contains a Cys3HisCys4 amino acid motif which binds two zinc cations. This protein domain contains from 40 to 60 amino acids...
motifStructural motifIn a chain-like biological molecule, such as a protein or nucleic acid, a structural motif is a supersecondary structure, which appears also in a variety of other molecules...
: recruits enzymes involved in ubiquitination - ProlineProlineProline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
-rich region: the site of interaction between Cbl and cytosolic proteins involved in Cbl's adaptor functions - C-terminal ubiquitin-associated domain (UBA domain): the site of ubiquitin binding
This domain structure and the tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
and serine
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
-rich content of the protein product is typical of an "adaptor molecule" used in cell signalling pathways.
Homologues
Three mammalian homologuesHomology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...
have been characterized, which all differ in their ability to function as adaptor proteins due to the differing lengths of their C-terminal UBA domains:
- c-Cbl: ubiquitously expressed, 906 amino acids in length.
- Cbl-b: ubiquitously expressed, 982 amino acids long in length.
- Cbl-c: lacks the UBA domain and is therefore only 474 amino acids in length. It is primarily expressed in epithelial cells however its function is poorly understood.
Interestingly, both c-Cbl and Cbl-b have orthologues
Homology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...
in D. melanogaster
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
(D-Cbl) and C. elegans
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
(Sli-1), hinting at a long evolutionary path for these proteins.
Ubiquitin ligase
Ubiquitination is the process of chemically attaching ubiquitinUbiquitin
Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...
monomers to a protein, thereby targeting it for degradation. As this is a multi-step process, several different enzymes are involved, the final one being a member of the E3 family of ligase
Ligase
In biochemistry, ligase is an enzyme that can catalyse the joining of two large molecules by forming a new chemical bond, usually with accompanying hydrolysis of a small chemical group dependent to one of the larger molecules...
s. Cbl functions as an E3 ligase, and therefore is able to catalyse the formation of a covalent bond between ubiquitin and Cbl's protein substrate - typically a receptor tyrosine kinase
Receptor tyrosine kinase
Receptor tyrosine kinases s are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins....
. The RING-finger domain mediates this transfer, however like other E3 ligases of the RING type no intermediate covalent bond is formed between ubiquitin and the RING-finger domain. The stepwise attachment of ubiquitin to the substrate receptor tyrosine kinase can lead to its removal from the plasma membrane and subsequent trafficking to the lysosome
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...
for degradation.
Interactions
Cbl gene has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with:
- Abl geneAbl geneV-abl Abelson murine leukemia viral oncogene homolog 1 also known as ABL1 is a protein that, in humans, is encoded by the ABL1 gene located on chromosome 9.- Function :...
, - ARHGEF7ARHGEF7Rho guanine nucleotide exchange factor 7 is a protein that in humans is encoded by the ARHGEF7 gene.-Interactions:ARHGEF7 has been shown to interact with GIT1, SHANK3, Cbl gene, SHANK1 and SHANK2.-External links:* Info with links in the...
, - C-MetC-METc-Met is a proto-oncogene that encodes a protein known as hepatocyte growth factor receptor . The hepatocyte growth factor receptor protein possesses tyrosine-kinase activity...
, - CD2APCD2APCD2-associated protein is a protein that in humans is encoded by the CD2AP gene.-Interactions:CD2AP has been shown to interact with NPHS2, Nephrin, Cbl gene and RAB4A.-Further reading:...
, - CSF1RColony stimulating factor 1 receptorColony stimulating factor 1 receptor , also known as macrophage colony-stimulating factor receptor , and CD115 , is a cell-surface protein encoded, in humans, by the CSF1R gene...
. - CRKCRK (gene)Adapter molecule crk also known as proto-oncogene c-Crk or p38 is a protein that in humans is encoded by the CRK gene.- Function :...
, - CRKLCRKLCrk-like protein is a protein that in humans is encoded by the CRKL gene.CrkL together with Crk participates in the Reelin signaling cascade downstream of DAB1.-Interactions:...
, - EGFREpidermal growth factor receptorThe epidermal growth factor receptor is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands...
,< - FRS2FRS2Fibroblast growth factor receptor substrate 2 is a protein that in humans is encoded by the FRS2 gene.-Interactions:FRS2 has been shown to interact with PRKCI, Grb2, PTPN11, Fibroblast growth factor receptor 1, TrkA, Cbl gene and SOS1....
, - FYNFYNProto-oncogene tyrosine-protein kinase Fyn is an enzyme that in humans is encoded by the FYN gene.This gene is a member of the protein-tyrosine kinase oncogene family. It encodes a membrane-associated tyrosine kinase that has been implicated in the control of cell growth...
, - Grb2Grb2Growth factor receptor-bound protein 2 also known as Grb2 is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene....
, - HCKHCKTyrosine-protein kinase HCK is an enzyme that in humans is encoded by the HCK gene.-Interactions:HCK has been shown to interact with BCR gene, ELMO1, Cbl gene, RAS p21 protein activator 1, RASA3, Granulocyte colony-stimulating factor receptor, ADAM15 and RAPGEF1.-Further reading:...
, - IGF1R,
- LCP2;Lymphocyte cytosolic protein 2Lymphocyte cytosolic protein 2 , also known as LCP2 or SLP-76, is a gene that encodes a signal-transducing adaptor protein.-Interactions:...
, - NCK1NCK1Cytoplasmic protein NCK1 is a protein that in humans is encoded by the NCK1 gene.-Interactions:NCK1 has been shown to interact with DNM1, EIF2B2, KHDRBS1, Lymphocyte cytosolic protein 2, EPH receptor B1, SOCS7, MINK1, MAP4K1, MAP4K4, Abl gene, WIPF1, RRAS, Wiskott-Aldrich syndrome protein,...
, - PDGFRAPDGFRAAlpha-type platelet-derived growth factor receptor is a protein that in humans is encoded by the PDGFRA gene.-Interactions:PDGFRA has been shown to interact with PDGFRB, PLCG1, Sodium-hydrogen antiporter 3 regulator 1, Cbl gene, CRK, Caveolin 1 and PDGFC.-Further reading:...
, - PIK3R1PIK3R1Phosphatidylinositol 3-kinase regulatory subunit alpha is an enzyme that in humans is encoded by the PIK3R1 gene.-Interactions:PIK3R1 has been shown to interact with EPH receptor A2, KHDRBS1, Lymphocyte cytosolic protein 2, Janus kinase 2, GAB2, CD117, BCAR1, CD28, SHB, EZR, PIK3CD, GAB1, HRAS,...
, - PIK3R2PIK3R2Phosphatidylinositol 3-kinase regulatory subunit beta is an enzyme that in humans is encoded by the PIK3R2 gene.-Interactions:PIK3R2 has been shown to interact with FYN, HER2/neu, Epidermal growth factor, Cbl gene, PIK3CD, CRKL and Macrophage colony-stimulating factor.-Further reading:...
, - PLCG1PLCG1Phospholipase C, gamma 1, also known as PLCG1, is a protein that in humans is encoded by the PLCG1 gene.-Function:The protein encoded by this gene catalyzes the formation of inositol 1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate...
, - PTK2BPTK2BProtein tyrosine kinase 2 beta is an enzyme that in humans is encoded by the PTK2B gene.-Protein:-Interactions:PTK2B has been shown to interact with PTPN11, PTPN6, PITPNM1, Gelsolin, Src, GRIN2A, Ewing sarcoma breakpoint region 1, RB1CC1, TGFB1I1, NPHP1, BCAR1, FYN, DLG4, DLG3, DDEF2, Cbl gene, RAS...
, - PTPN11PTPN11Tyrosine-protein phosphatase non-receptor type 11 also known as protein-tyrosine phosphatase 1D or protein-tyrosine phosphatase 2C is an enzyme that in humans is encoded by the PTPN11 gene. PTPN11 is a protein tyrosine phosphatase Shp2.PTPN11 is a member of the protein tyrosine phosphatase ...
, - SH2B2SH2B2SH2B adapter protein 2 is a protein that in humans is encoded by the SH2B2 gene.-Interactions:SH2B2 has been shown to interact with TrkA and Cbl gene.-Further reading:...
, - SH3KBP1SH3KBP1SH3 domain-containing kinase-binding protein 1 is an enzyme that in humans is encoded by the SH3KBP1 gene.-Interactions:SH3KBP1 has been shown to interact with B-cell linker, Grb2, SH3GLB2, SH3GL3, SH3GL2, BCAR1, Epidermal growth factor receptor, CBLB, Cbl gene, SOS1, CRK and PAK2.-Further reading:...
- SHC1SHC1SHC-transforming protein 1 is a protein that in humans is encoded by the SHC1 gene. SHC has been found to be important in the regulation of apoptosis and drug resistance in mammalian cells....
, - SLA2SLA2Src-like-adapter 2 is a protein that in humans is encoded by the SLA2 gene.-Further reading:...
, - SORBS1SORBS1Sorbin and SH3 domain-containing protein 1 is a protein that in humans is encoded by the SORBS1 gene.-Interactions:SORBS1 has been shown to interact with FLOT1, Vinculin, INSM1, MLLT4, Cbl gene and INPPL1.-Further reading:...
, - SORBS2SORBS2Sorbin and SH3 domain-containing protein 2 is a protein that in humans is encoded by the SORBS2 gene.-Interactions:SORBS2 has been shown to interact with PTK2B, Cbl gene, ABL2 and Abl gene.-Further reading:...
, - SPRY2SPRY2Sprouty homolog 2 , also known as SPRY2, is a protein which in humans is encoded by the SPRY2 gene.- Function :This gene encodes a protein belonging to the sprouty family...
, - SykSykSpleen tyrosine kinase, also known as Syk, is an enyzme which in humans is encoded by the SYK gene.- Function :SYK, along with Zap-70, is a member of the Syk family of tyrosine kinases...
, - UBE2L3UBE2L3Ubiquitin-conjugating enzyme E2 L3 is a protein that in humans is encoded by the UBE2L3 gene.-Interactions:UBE2L3 has been shown to interact with UBOX5, ARIH1, Cbl gene, UBE3A and NEDD4.-Further reading:...
, - VAV1VAV1Proto-oncogene vav is a protein that in humans is encoded by the VAV1 gene.-Interactions:VAV1 has been shown to interact with Ku70, PLCG1, Lymphocyte cytosolic protein 2, Janus kinase 2, SIAH2, S100B, Abl gene, ARHGDIB, SHB, PIK3R1, PRKCQ, Grb2, MAPK1, Syk, Linker of activated T cells, Cbl gene and...
, - YWHABYWHAB14-3-3 protein beta/alpha is a protein that in humans is encoded by the YWHAB gene.-Interactions:YWHAB has been shown to interact with CDC25A, CDC25B, BRAF, C-Raf, RPS6KA1, EPB41L3, CD29, Wee1-like protein kinase, PTPN3, Protein kinase Mζ, MAPK7, TESK1, TNFAIP3, Cbl gene, HDAC4 and KCNK3.-Further...
, - YWHAQYWHAQ14-3-3 protein theta is a protein that in humans is encoded by the YWHAQ gene.-Interactions:YWHAQ has been shown to interact with MEF2D, Bcl-2-associated X protein, CRTC2, C-Raf, Histone deacetylase 5, NRIP1, Protein kinase Mζ, UCP3, PFKFB2, Telomerase reverse transcriptase, Bcl-2-associated death...
, and - ZAP-70ZAP-70ZAP-70 is an abbreviation for Zeta-chain-associated protein kinase 70 . The protein is a member in the protein-tyrosine kinase family...
,