CBL (gene)

Mammalian gene

"CBL2" redirects here. For the airport in Canada, see Severn Bridge/Buck Lake Water Aerodrome.

CBL

| Available structures

PDB| Ortholog search: PDBe RCSB
| List of PDB id codes

1B47, 1FBV, 1YVH, 2CBL, 2JUJ, 2K4D, 2OO9, 2Y1M, 2Y1N, 3BUM, 3BUN, 3BUO, 3BUW, 3BUX, 3OB1, 3OB2, 3PLF, 4A49, 4A4B, 4A4C, 4GPL

Identifiers
Aliases| CBL, C-CBL2, FRA11B, NSLL, RNF55, Cbl proto-oncogene
External IDs| OMIM: 165360; MGI: 88279; HomoloGene: 3802; GeneCards: CBL; OMA:CBL - orthologs
| Gene location (Human)

Chr.| Chromosome 11 (human)[1]

Band| 11q23.3| Start| 119,206,298 bp[1]
End| 119,313,926 bp[1]
| Gene location (Mouse)

Chr.| Chromosome 9 (mouse)[2]

Band| 9 A5.1- A5.2|9 24.72 cM| Start| 44,054,273 bp[2]
End| 44,145,346 bp[2]
| RNA expression pattern

Bgee| | Human| Mouse (ortholog)

|

| Top expressed in

* gonad

* trigeminal ganglion

* testicle

* trabecular bone

* saphenous vein

* spinal ganglia

* superficial temporal artery

* nipple

* blood

* visceral pleura

| Top expressed in

* thymus

* granulocyte

* Rostral migratory stream

* spermatocyte

* tail of embryo

* spermatid

* mesenteric lymph nodes

* lateral septal nucleus

* anterior amygdaloid area

* blood

More reference expression data
BioGPS| |

More reference expression data
| Gene ontology

Molecular function|

* calcium ion binding
* DNA-binding transcription factor activity
* phosphotyrosine residue binding
* signal transducer activity
* metal ion binding
* ubiquitin-protein transferase activity
* protein binding
* ephrin receptor binding
* SH3 domain binding
* phosphatidylinositol 3-kinase regulatory subunit binding
* transferase activity
* receptor tyrosine kinase binding
* ubiquitin protein ligase activity
* cadherin binding
* epidermal growth factor receptor binding
* protein kinase binding
* protein tyrosine kinase binding

Cellular component|

* membrane
* plasma membrane
* nucleus
* perinuclear region of cytoplasm
* flotillin complex
* growth cone
* cytoplasm
* cytosol
* focal adhesion
* axon
* mast cell granule
* membrane raft
* Golgi apparatus
* cilium
* cell projection

Biological process|

* positive regulation of receptor-mediated endocytosis
* negative regulation of epidermal growth factor receptor signaling pathway
* epidermal growth factor receptor signaling pathway
* negative regulation of apoptotic process
* regulation of signaling
* fibroblast growth factor receptor signaling pathway
* cell surface receptor signaling pathway
* protein ubiquitination
* positive regulation of phosphatidylinositol 3-kinase signaling
* transforming growth factor beta receptor signaling pathway
* cellular response to DNA damage stimulus
* cellular response to nerve growth factor stimulus
* cellular response to platelet-derived growth factor stimulus
* positive regulation of epidermal growth factor receptor signaling pathway
* regulation of transcription, DNA-templated
* neuron death
* cellular response to oxygen-glucose deprivation
* response to activity
* response to starvation
* response to ethanol
* protein polyubiquitination
* protein monoubiquitination
* negative regulation of epidermal growth factor-activated receptor activity
* male gonad development
* response to gamma radiation
* response to testosterone
* entry of bacterium into host cell
* mast cell degranulation
* response to antibiotic
* membrane organization
* negative regulation of neuron death
* cytokine-mediated signaling pathway
* interleukin-6-mediated signaling pathway
* ubiquitin-dependent protein catabolic process
* signal transduction
* regulation of Rap protein signal transduction
* cellular response to epidermal growth factor stimulus
* regulation of platelet-derived growth factor receptor-alpha signaling pathway

Sources:Amigo / QuickGO
| Orthologs

Species| Human| Mouse
Entrez| |

867

12402

Ensembl| |

ENSG00000110395

ENSMUSG00000034342

UniProt| |

P22681

P22682

RefSeq (mRNA)| |

NM_005188

NM_007619

RefSeq (protein)| |

NP_005179

NP_031645

Location (UCSC)| Chr 11: 119.21 – 119.31 Mb| Chr 9: 44.05 – 44.15 Mb
PubMed search| [3]| [4]
Wikidata
| View/Edit Human| View/Edit Mouse

|

E3 ubiquitin-protein ligase CBL is an enzyme that is humans is encoded by the CBL (Casitas B-lineage Lymphoma) gene. CBL gene is the founding member the Cbl family. The protein CBL which is an E3 ubiquitin-protein ligase involved in cell signalling and protein ubiquitination. Mutations to this gene have been implicated in a number of human cancers, particularly acute myeloid leukaemia.[5]

## Discovery

[edit]

In 1989 a virally encoded portion of the chromosomal mouse Cbl gene was the first member of the Cbl family to be discovered[6] and was named v-Cbl to distinguish it from normal mouse c-Cbl. The virus used in the experiment was a mouse-tropic strain of Murine leukemia virus isolated from the brain of a mouse captured at Lake Casitas, California known as Cas-Br-M,[7] and was found to have excised approximately a third of the original c-Cbl gene from a mouse into which it was injected. Sequencing revealed that the portion carried by the retrovirus encoded a tyrosine kinase binding domain, and that this was the oncogenic form as retroviruses carrying full-length c-Cbl did not induce tumor 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

[edit]

Full length c-Cbl has been found to consist of several regions encoding for functionally distinct protein domains:

* N-terminal tyrosine kinase binding domain (TKB domain): determines the protein which it can bind to
* RING finger domain motif: recruits enzymes involved in ubiquitination
* Proline-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 and serine-rich content of the protein product is typical of an "adaptor molecule" used in cell signalling pathways.[8]

## Homologues

[edit]

Three mammalian homologues 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:

1. c-Cbl: ubiquitously expressed, 906 and 913 amino acids in length in humans and mice respectively
2. Cbl-b: ubiquitously expressed, 982 amino acids long.
3. 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.

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.[8]

## Function

[edit]

### Ubiquitin ligase

[edit]

Ubiquitination is the process of chemically attaching ubiquitin 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 ligases. 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.

## Interactions

[edit]

Cbl gene has been shown to interact with:

* Abl gene,[9][10]
* ARHGEF7,[11]
* C-Met,[12][13]
* CD2AP,[14][15][16]
* CSF1R.[17]
* CRK,[18][19]
* CRKL,[20][21][22][23][24][25][26][27]
* EGFR,[12]<[28][29]
* FRS2,[30]
* FYN,[24][31]
* Grb2,[12][18][19][20][30][32][33][34][35][36][37][38][39]
* HCK,[40][41]
* IGF1R,[42]
* LCP2,[20][43]
* NCK1,[9][20]
* PDGFRA,[44]
* PIK3R1,[18][45][46]
* PIK3R2,[21][47]
* PLCG1,[28][48]
* PTK2B,[14][49]
* PTPN11,[50]
* SH2B2,[12][51]
* SH3KBP1[13][52][53][54][55]
* SHC1,[18][32]
* SLA2,[56]
* SORBS1,[14][57]
* SORBS2,[10][14]
* SPRY2,[12][58][59]
* Syk,[60][61][62]
* UBE2L3,[58][63][64]
* VAV1,[61][65]
* YWHAB,[36]
* YWHAQ,[66][67] and
* ZAP-70,[68][69]

## References

[edit]

1. ^ a b c GRCh38: Ensembl release 89: ENSG00000110395 – Ensembl, May 2017
2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000034342 – Ensembl, May 2017
3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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6. ^ Langdon WY, Hartley JW, Klinken SP, Ruscetti SK, Morse HC (Feb 1989). "v-cbl, an oncogene from a dual-recombinant murine retrovirus that induces early B-lineage lymphomas". Proceedings of the National Academy of Sciences of the United States of America. 86 (4): 1168–1172\. Bibcode:1989PNAS...86.1168L. doi:10.1073/pnas.86.4.1168. PMC 286647. PMID 2784003.
7. ^ Hartley J, Rowe W (July 1976). "Naturally occurring murine leukemia viruses in wild mice: characterization of a new "amphotropic" class". Journal of Virology. 19 (1): 19–25\. doi:10.1128/JVI.19.1.19-25.1976. PMC 354828. PMID 59816.
8. ^ a b Schmidt MH, Dikic I (Dec 2005). "The Cbl interactome and its functions". Nature Reviews. Molecular Cell Biology. 6 (12): 907–918\. doi:10.1038/nrm1762. PMID 16227975. S2CID 1527924.
9. ^ a b Miyoshi-Akiyama T, Aleman LM, Smith JM, Adler CE, Mayer BJ (July 2001). "Regulation of Cbl phosphorylation by the Abl tyrosine kinase and the Nck SH2/SH3 adaptor". Oncogene. 20 (30): 4058–4069\. doi:10.1038/sj.onc.1204528. PMID 11494134.
10. ^ a b Soubeyran P, Barac A, Szymkiewicz I, Dikic I (February 2003). "Cbl-ArgBP2 complex mediates ubiquitination and degradation of c-Abl". The Biochemical Journal. 370 (Pt 1): 29–34\. doi:10.1042/BJ20021539. PMC 1223168. PMID 12475393.
11. ^ Flanders JA, Feng Q, Bagrodia S, Laux MT, Singavarapu A, Cerione RA (August 2003). "The Cbl proteins are binding partners for the Cool/Pix family of p21-activated kinase-binding proteins". FEBS Letters. 550 (1–3): 119–123\. Bibcode:2003FEBSL.550..119F. doi:10.1016/S0014-5793(03)00853-6. PMID 12935897. S2CID 46540220.1–3&rft.pages=119-123&rft.date=2003-08&rft_id=info:doi/10.1016/S0014-5793(03)00853-6&rft_id=https://api.semanticscholar.org/CorpusID:46540220#id-name=S2CID&rft_id=info:pmid/12935897&rft_id=info:bibcode/2003FEBSL.550..119F&rft.aulast=Flanders&rft.aufirst=JA&rft.au=Feng,+Q&rft.au=Bagrodia,+S&rft.au=Laux,+MT&rft.au=Singavarapu,+A&rft.au=Cerione,+RA&rfr_id=info:sid/en.wikipedia.org:CBL+(gene)" class="Z3988">
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55. ^ Borinstein SC, Hyatt MA, Sykes VW, Straub RE, Lipkowitz S, Boulter J, et al. (December 2000). "SETA is a multifunctional adapter protein with three SH3 domains that binds Grb2, Cbl, and the novel SB1 proteins". Cellular Signalling. 12 (11–12): 769–779\. doi:10.1016/S0898-6568(00)00129-7. PMID 11152963.11–12&rft.pages=769-779&rft.date=2000-12&rft_id=info:doi/10.1016/S0898-6568(00)00129-7&rft_id=info:pmid/11152963&rft.aulast=Borinstein&rft.aufirst=SC&rft.au=Hyatt,+MA&rft.au=Sykes,+VW&rft.au=Straub,+RE&rft.au=Lipkowitz,+S&rft.au=Boulter,+J&rft.au=Bogler,+O&rfr_id=info:sid/en.wikipedia.org:CBL+(gene)" class="Z3988">
56. ^ Pandey A, Ibarrola N, Kratchmarova I, Fernandez MM, Constantinescu SN, Ohara O, et al. (May 2002). "A novel Src homology 2 domain-containing molecule, Src-like adapter protein-2 (SLAP-2), which negatively regulates T cell receptor signaling". Journal of Biological Chemistry. 277 (21): 19131–19138\. doi:10.1074/jbc.M110318200. PMID 11891219.
57. ^ Vandenbroere I, Paternotte N, Dumont JE, Erneux C, Pirson I (January 2003). "The c-Cbl-associated protein and c-Cbl are two new partners of the SH2-containing inositol polyphosphate 5-phosphatase SHIP2". Biochemical and Biophysical Research Communications. 300 (2): 494–500\. doi:10.1016/S0006-291X(02)02894-2. PMID 12504111.
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## Further reading

[edit]

* Smit L, Borst J (1997). "The Cbl family of signal transduction molecules". Critical Reviews in Oncogenesis. 8 (4): 359–379\. doi:10.1615/critrevoncog.v8.i4.50. PMID 9622055.
* Lupher ML, Andoniou CE, Bonita D, Miyake S, Band H (Apr 1998). "The c-Cbl oncoprotein". The International Journal of Biochemistry & Cell Biology. 30 (4): 439–444\. doi:10.1016/S1357-2725(97)00075-7. PMID 9675877.
* Fang N, Fang D, Wang HY, Altman A, Liu YC (2002). "Regulation of immune responses by E3 ubiquitin-protein ligases". Current Directions in Autoimmunity. 5: 161–175\. doi:10.1159/000060552. ISBN 978-3-8055-7308-5. PMID 11826757. `{{cite journal}}`: Cite journal requires `|journal=` (help)

## External links

[edit]

* Quips article describing CBL function at PDBe
* OMIM entries on NOONAN SYNDROME-LIKE DISORDER WITH OR WITHOUT JUVENILE MYELOMONOCYTIC LEUKEMIA and CBL
* Human CBL genome location and CBL gene details page in the UCSC Genome Browser.

* v
* t
* e

PDB gallery

* 1b47: STRUCTURE OF THE N-TERMINAL DOMAIN OF CBL IN COMPLEX WITH ITS BINDING SITE IN ZAP-70

* 1fbv: STRUCTURE OF A CBL-UBCH7 COMPLEX: RING DOMAIN FUNCTION IN UBIQUITIN-PROTEIN LIGASES

* 1yvh: Crystal Structure of the c-Cbl TKB Domain in Complex with the APS pTyr-618 Phosphopeptide

* 2cbl: N-TERMINAL DOMAIN OF CBL IN COMPLEX WITH ITS BINDING SITE ON ZAP-70

* 2oo9: crystal structure of the UBA domain from human c-Cbl ubiquitin ligase

* v
* t
* e

Tumor suppressor genes and Oncogenes

Ligand|

| Growth factors|

| ONCO|

* c-Sis/PDGF
* HGF

|

Receptor|

| Wnt signaling pathway|

| TSP|

* CDH1

|

Hedgehog signaling pathway|

| TSP|

* PTCH1

|

TGF beta signaling pathway|

| TSP|

* TGF beta receptor 2

|

Receptor tyrosine kinase|

| ONCO|

* ErbB/c-ErbB
* HER2/neu
* Her 3
* c-Met
* c-Ret

|

JAK-STAT signaling pathway|

| ONCO|

* c-Kit
* Flt3

|

Intracellular signaling P+Ps|

| Wnt signaling pathway|

| ONCO|

* Beta-catenin

|

TSP|

* APC

TGF beta signaling pathway|

| TSP|

* SMAD2
* SMAD4

|

Akt/PKB signaling pathway|

| ONCO|

* c-Akt

|

TSP|

* PTEN

Hippo signaling pathway|

| TSP|

* Neurofibromin 2/Merlin

|

MAPK/ERK pathway|

| ONCO|

* c-Ras
* HRAS
* c-Raf

|

TSP|

* Neurofibromin 1

Other/unknown|

| ONCO|

* c-Src

|

TSP|

* Maspin

Nucleus|

| Cell cycle|

| ONCO|

* CDK4
* Cyclin D
* Cyclin E

|

TSP|

* p53
* pRb
* WT1
* p16/p14arf

DNA repair/Fanconi|

| TSP|

* BRCA1
* BRCA2

|

Ubiquitin ligase|

| ONCO|

* CBL
* MDM2

|

TSP|

* VHL

Transcription factor|

| ONCO|

* AP-1
* c-Fos
* c-Jun
* c-Myc

|

TSP|

* KLF6

Mitochondrion|

| Apoptosis inhibitor|

* SDHB
* SDHD

|

Other/ungrouped|

* c-Bcl-2
* Notch
* Stathmin

* v
* t
* e

Posttranslational modification

Chaperones/
protein folding|

| Heat shock proteins/
Chaperonins|

* Hsp10/GroES
* Hsp27
* Hsp47
* HSP60/GroEL

* Hsp40/DnaJ
* A1
* A2
* A3
* B1
* B2
* B11
* B4
* B6
* B9
* C1
* C3
* C5
* C6
* C7
* C10
* C11
* C13
* C14
* C19

* Hsp70
* 1A
* 1B
* 1L
* 2
* 4
* 4L
* 5
* 6
* 7
* 8
* 9
* 12A
* 14

* Hsp90
* α1
* α2
* β
* ER
* TRAP1

|

Other|

* Alpha crystallin
* Clusterin
* Survival of motor neuron
* SMN1
* SMN2

Protein targeting|

* Signal peptide
* Mitochondrial targeting signal

Ubiquitin
(ubiquitylation)|

* E1 Ubiquitin-activating enzyme
* UBA1
* UBA2
* UBA3
* UBA5
* UBA6
* UBA7
* ATG7
* NAE1
* SAE1

* E2 Ubiquitin-conjugating enzyme
* A
* B
* C
* D1
* D2
* D3
* E1
* E2
* E3
* G1
* G2
* H
* I
* J1
* J2
* K
* L1
* L2
* L3
* L4
* L6
* M
* N
* O
* Q1
* Q2
* R1 (CDC34)
* R2
* S
* V1
* V2
* Z

* E3 Ubiquitin ligase
* VHL
* Cullin
* CBL
* MDM2
* FANCL
* UBR1

* Deubiquitinating enzyme: Ataxin 3
* USP6
* CYLD

* ATG3
* BIRC6
* UFC1

Ubiquitin-like proteins
(UBL)|

| SUMO protein
(SUMOylation)|

* E1 SUMO-activating enzyme
* SAE1
* SAE2

* E2 SUMO-conjugating enzyme
* UBC9

* E3 SUMO ligase
* PIAS1
* PIAS2
* PIAS3
* PIAS4

|

Other|

* ISG15
* URM1
* UFM1
* NEDD8 (neddylation)
* FAT10
* ATG8
* ATG12
* FUB1
* MUB
* UBL5

* Prokaryotic ubiquitin-like protein

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*[t]: Discuss this template
*[e]: Edit this template