P22682

SS
Gene name
Cbl
Protein name
E3 ubiquitin-protein ligase CBL
Names
EC 2.3.2.27 , Casitas B-lineage lymphoma proto-oncogene , Proto-oncogene c-Cbl , RING-type E3 ubiquitin transferase CBL , Signal transduction protein CBL
Species
Mus musculus (Mouse)
KEGG Pathway
mmu:12402
EC number
2.3.2.27: Aminoacyltransferases
Protein Class

Descriptions

Cbls are adaptor proteins with RING ubiquitin ligase activity, which function as a negative regulator of many signaling pathways. In human CBL, the phosphorylation of Y371 is essential in regulation of the E3 activity of CBL. When Y371 is unmodified, the RING domain is spatially restricted to regions distal from the TKBD substrate-binding site. Phosphorylation facilitates LHR (linker-loop1 (LL1), linker-helix (LH) and linker-loop2 (LL2)) conformational changes that enable the RING domain to approach the N-terminal tyrosine kinase-binding domain (TKBD) substrate-binding site, leading to an increased activity. Specifically, the absence of LH-TKBD contact enables dramatic movement of the RING domain, bringing E2 closer to the TKBD substrate-binding site. Restricting and freeing the RING domain may be a general mechanism for regulating other RING E3s.

Autoinhibitory domains (AIDs)

362-373 (LH region) SS

Target domain

45-351 (TKBD)

Relief mechanism

PTM

Assay

381-432 (RING domain) SS

Target domain

47-349 (TKB domain)

Relief mechanism

PTM

Assay

Accessory elements

No accessory elements

References

Autoinhibited structure

Activated structure

2 structures for P22682

Entry ID Method Resolution Chain Position Source
2D9S NMR - A/B 863-902 PDB
AF-P22682-F1 Predicted AlphaFoldDB

48 variants for P22682

Variant ID(s) Position Change Description Diseaes Association Provenance
rs3389007313 241 I>N No EVA
rs3389032619 262 T>S No EVA
rs3389041995 265 G>V No EVA
rs3399749028 287 G>A No EVA
rs3389036619 300 Q>E No EVA
rs3388986057 301 W>* No EVA
rs3389037274 325 A>P No EVA
364 E>del oncogenic variant 70Z/3 [UniProt] No
rs3389040366 428 V>M No EVA
rs3389012941 489 A>D No EVA
rs3389027381 489 A>T No EVA
rs3547295013 509 A>S No EVA
rs3389027401 528 D>V No EVA
rs3547258979 534 P>S No EVA
rs3547216374 552 V>A No EVA
rs3547383153 558 P>L No EVA
rs3547259696 561 R>C No EVA
rs3547241581 583 R>C No EVA
rs3547201409 590 S>F No EVA
rs3389046290 597 P>L No EVA
rs3547219710 601 P>L No EVA
rs3547201492 606 P>L No EVA
rs3547259191 611 E>G No EVA
rs224974500 615 R>Q No EVA
rs3547259736 618 L>F No EVA
rs3547246776 624 S>T No EVA
rs3547259491 632 V>F No EVA
rs3388986031 643 T>N No EVA
rs3389032024 644 S>F No EVA
rs236909014 646 T>N No EVA
rs3400169368 671 I>L No EVA
rs3400077706 671 I>M No EVA
rs3399533273 673 S>N No EVA
rs3547330979 743 I>M No EVA
rs3547330987 746 Q>K No EVA
rs3547383020 827 R>W No EVA
rs3547203497 834 R>P No EVA
rs3547259202 849 G>R No EVA
rs3547198141 853 A>V No EVA
rs3389032015 855 P>H No EVA
rs3547216117 860 P>L No EVA
rs3389038970 865 S>L No EVA
rs1134142566 867 E>* No EVA
rs3547259198 873 S>T No EVA
rs1135315060 880 D>N No EVA
rs1132936140 887 I>N No EVA
rs1132341532 895 A>T No EVA
rs3547203715 900 R>W No EVA

1 associated diseases with P22682

Without disease ID

8 regional properties for P22682

Type Name Position InterPro Accession
domain Zinc finger, RING-type 379 - 418 IPR001841
domain Adaptor protein Cbl, N-terminal helical 49 - 173 IPR003153
domain Adaptor protein Cbl, EF hand-like 177 - 260 IPR014741
domain Adaptor protein Cbl, SH2-like domain 254 - 350 IPR014742
domain Ubiquitin-associated domain 863 - 902 IPR015940
conserved_site Zinc finger, RING-type, conserved site 394 - 403 IPR017907
domain Zinc finger, C3HC4 RING-type 379 - 417 IPR018957
domain Adaptor protein Cbl, PTB domain 45 - 349 IPR024159

Functions

Description
EC Number 2.3.2.27 Aminoacyltransferases
Subcellular Localization
  • Cytoplasm
  • Cell membrane
  • Cell projection, cilium
  • Golgi apparatus
  • Colocalizes with FGFR2 in lipid rafts at the cell membrane
PANTHER Family
PANTHER Subfamily
PANTHER Protein Class
PANTHER Pathway Category No pathway information available

10 GO annotations of cellular component

Name Definition
axon The long process of a neuron that conducts nerve impulses, usually away from the cell body to the terminals and varicosities, which are sites of storage and release of neurotransmitter.
cilium A specialized eukaryotic organelle that consists of a filiform extrusion of the cell surface and of some cytoplasmic parts. Each cilium is largely bounded by an extrusion of the cytoplasmic (plasma) membrane, and contains a regular longitudinal array of microtubules, anchored to a basal body.
cytosol The part of the cytoplasm that does not contain organelles but which does contain other particulate matter, such as protein complexes.
flotillin complex A protein complex that contains flotillin-1 and flotillin-2, and may contain associated proteins. Flotillins associate into membrane microdomains resembling caveolae.
focal adhesion A cell-substrate junction that anchors the cell to the extracellular matrix and that forms a point of termination of actin filaments. In insects focal adhesion has also been referred to as hemi-adherens junction (HAJ).
Golgi apparatus A membrane-bound cytoplasmic organelle of the endomembrane system that further processes the core oligosaccharides (e.g. N-glycans) added to proteins in the endoplasmic reticulum and packages them into membrane-bound vesicles. The Golgi apparatus operates at the intersection of the secretory, lysosomal, and endocytic pathways.
growth cone The migrating motile tip of a growing neuron projection, where actin accumulates, and the actin cytoskeleton is the most dynamic.
membrane raft Any of the small (10-200 nm), heterogeneous, highly dynamic, sterol- and sphingolipid-enriched membrane domains that compartmentalize cellular processes. Small rafts can sometimes be stabilized to form larger platforms through protein-protein and protein-lipid interactions.
perinuclear region of cytoplasm Cytoplasm situated near, or occurring around, the nucleus.
plasma membrane The membrane surrounding a cell that separates the cell from its external environment. It consists of a phospholipid bilayer and associated proteins.

9 GO annotations of molecular function

Name Definition
calcium ion binding Binding to a calcium ion (Ca2+).
ephrin receptor binding Binding to an ephrin receptor.
phosphatidylinositol 3-kinase regulatory subunit binding Binding to a regulatory subunit of phosphatidylinositol 3-kinase. The regulatory subunit associates with the catalytic subunit to regulate both its activity and subcellular location.
phosphotyrosine residue binding Binding to a phosphorylated tyrosine residue within a protein.
protein kinase binding Binding to a protein kinase, any enzyme that catalyzes the transfer of a phosphate group, usually from ATP, to a protein substrate.
protein tyrosine kinase binding Binding to protein tyrosine kinase.
receptor tyrosine kinase binding Binding to a receptor that possesses protein tyrosine kinase activity.
SH3 domain binding Binding to a SH3 domain (Src homology 3) of a protein, small protein modules containing approximately 50 amino acid residues found in a great variety of intracellular or membrane-associated proteins.
ubiquitin protein ligase activity Catalysis of the transfer of ubiquitin to a substrate protein via the reaction X-ubiquitin + S -> X + S-ubiquitin, where X is either an E2 or E3 enzyme, the X-ubiquitin linkage is a thioester bond, and the S-ubiquitin linkage is an amide bond

27 GO annotations of biological process

Name Definition
bone resorption The process in which specialized cells known as osteoclasts degrade the organic and inorganic portions of bone, and endocytose and transport the degradation products.
cell surface receptor signaling pathway The series of molecular signals initiated by activation of a receptor on the surface of a cell. The pathway begins with binding of an extracellular ligand to a cell surface receptor, or for receptors that signal in the absence of a ligand, by ligand-withdrawal or the activity of a constitutively active receptor. The pathway ends with regulation of a downstream cellular process, e.g. transcription.
cellular response to hypoxia Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a stimulus indicating lowered oxygen tension. Hypoxia, defined as a decline in O2 levels below normoxic levels of 20.8 - 20.95%, results in metabolic adaptation at both the cellular and organismal level.
cellular response to nerve growth factor stimulus A process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a nerve growth factor stimulus.
cellular response to platelet-derived growth factor stimulus Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a platelet-derived growth factor stimulus.
DNA damage response Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a stimulus indicating damage to its DNA from environmental insults or errors during metabolism.
male gonad development The process whose specific outcome is the progression of the male gonad over time, from its formation to the mature structure.
mast cell degranulation The regulated exocytosis of secretory granules containing preformed mediators such as histamine, serotonin, and neutral proteases by a mast cell.
negative regulation of apoptotic process Any process that stops, prevents, or reduces the frequency, rate or extent of cell death by apoptotic process.
negative regulation of epidermal growth factor receptor signaling pathway Any process that stops, prevents, or reduces the frequency, rate or extent of epidermal growth factor receptor signaling pathway activity.
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction Any process that activates or increases the frequency, rate or extent of protein kinase B signaling, a series of reactions mediated by the intracellular serine/threonine kinase protein kinase B.
positive regulation of receptor-mediated endocytosis Any process that activates or increases the frequency, rate or extent of receptor mediated endocytosis, the uptake of external materials by cells, utilizing receptors to ensure specificity of transport.
protein autoubiquitination The ubiquitination by a protein of one or more of its own amino acid residues, or residues on an identical protein. Ubiquitination occurs on the lysine residue by formation of an isopeptide crosslink.
protein monoubiquitination Addition of a single ubiquitin group to a protein.
protein phosphorylation The process of introducing a phosphate group on to a protein.
protein polyubiquitination Addition of multiple ubiquitin groups to a protein, forming a ubiquitin chain.
protein ubiquitination The process in which one or more ubiquitin groups are added to a protein.
regulation of platelet-derived growth factor receptor-alpha signaling pathway Any process that modulates the frequency, rate or extent of platelet-derived growth factor receptor-alpha signaling pathway.
regulation of Rap protein signal transduction Any process that modulates the frequency, rate or extent of Rap protein signal transduction.
response to activity Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of an activity stimulus.
response to ethanol Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of an ethanol stimulus.
response to gamma radiation Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a gamma radiation stimulus. Gamma radiation is a form of electromagnetic radiation (EMR) or light emission of a specific frequency produced from sub-atomic particle interaction, such as electron-positron annihilation and radioactive decay. Gamma rays are generally characterized as EMR having the highest frequency and energy, and also the shortest wavelength, within the electromagnetic radiation spectrum.
response to starvation Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a starvation stimulus, deprivation of nourishment.
response to testosterone Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a testosterone stimulus.
signal transduction The cellular process in which a signal is conveyed to trigger a change in the activity or state of a cell. Signal transduction begins with reception of a signal (e.g. a ligand binding to a receptor or receptor activation by a stimulus such as light), or for signal transduction in the absence of ligand, signal-withdrawal or the activity of a constitutively active receptor. Signal transduction ends with regulation of a downstream cellular process, e.g. regulation of transcription or regulation of a metabolic process. Signal transduction covers signaling from receptors located on the surface of the cell and signaling via molecules located within the cell. For signaling between cells, signal transduction is restricted to events at and within the receiving cell.
ubiquitin-dependent endocytosis Endocytosis of a protein that requires the substrate to be modified by ubiquitination. Several plasma membrane proteins, including cell surface permeases and some receptors, are targeted for internalization by endocytosis, and are thereafter delivered to the vacuole or lysosome, where they are degraded.
ubiquitin-dependent protein catabolic process The chemical reactions and pathways resulting in the breakdown of a protein or peptide by hydrolysis of its peptide bonds, initiated by the covalent attachment of a ubiquitin group, or multiple ubiquitin groups, to the protein.

7 homologous proteins in AiPD

UniProt AC Gene Name Protein Name Species Evidence Code
Q13191 CBLB E3 ubiquitin-protein ligase CBL-B Homo sapiens (Human) EV
Q9ULV8 CBLC E3 ubiquitin-protein ligase CBL-C Homo sapiens (Human) SS
P22681 CBL E3 ubiquitin-protein ligase CBL Homo sapiens (Human) EV
Q3TTA7 Cblb E3 ubiquitin-protein ligase CBL-B Mus musculus (Mouse) SS
Q80XL1 Cblc E3 ubiquitin-protein ligase CBL-C Mus musculus (Mouse) SS
Q8K4S7 Cblb E3 ubiquitin-protein ligase CBL-B Rattus norvegicus (Rat) SS
G3V8H4 Cblc E3 ubiquitin-protein ligase CBL-C Rattus norvegicus (Rat) SS
10 20 30 40 50 60
MAGNVKKSSG AGGGGSGGSG AGGLIGLMKD AFQPHHHHHH LSPHPPCTVD KKMVEKCWKL
70 80 90 100 110 120
MDKVVRLCQN PKLALKNSPP YILDLLPDTY QHLRTVLSRY EGKMETLGEN EYFRVFMENL
130 140 150 160 170 180
MKKTKQTISL FKEGKERMYE ENSQPRRNLT KLSLIFSHML AELKGIFPSG LFQGDTFRIT
190 200 210 220 230 240
KADAAEFWRK AFGEKTIVPW KSFRQALHEV HPISSGLEAM ALKSTIDLTC NDYISVFEFD
250 260 270 280 290 300
IFTRLFQPWS SLLRNWNSLA VTHPGYMAFL TYDEVKARLQ KFIHKPGSYI FRLSCTRLGQ
310 320 330 340 350 360
WAIGYVTADG NILQTIPHNK PLFQALIDGF REGFYLFPDG RNQNPDLTGL CEPTPQDHIK
370 380 390 400 410 420
VTQEQYELYC EMGSTFQLCK ICAENDKDVK IEPCGHLMCT SCLTSWQESE GQGCPFCRCE
430 440 450 460 470 480
IKGTEPIVVD PFDPRGSGSL LRQGAEGAPS PNYDDDDDER ADDSLFMMKE LAGAKVERPS
490 500 510 520 530 540
SPFSMAPQAS LPPVPPRLDL LQQRAPVPAS TSVLGTASKA ASGSLHKDKP LPIPPTLRDL
550 560 570 580 590 600
PPPPPPDRPY SVGAETRPQR RPLPCTPGDC PSRDKLPPVP SSRPGDSWLS RPIPKVPVAT
610 620 630 640 650 660
PNPGDPWNGR ELTNRHSLPF SLPSQMEPRA DVPRLGSTFS LDTSMTMNSS PVAGPESEHP
670 680 690 700 710 720
KIKPSSSANA IYSLAARPLP MPKLPPGEQG ESEEDTEYMT PTSRPVGVQK PEPKRPLEAT
730 740 750 760 770 780
QSSRACDCDQ QIDSCTYEAM YNIQSQALSV AENSASGEGN LATAHTSTGP EESENEDDGY
790 800 810 820 830 840
DVPKPPVPAV LARRTLSDIS NASSSFGWLS LDGDPTNFNE GSQVPERPPK PFPRRINSER
850 860 870 880 890 900
KASSYQQGGG ATANPVATAP SPQLSSEIER LMSQGYSYQD IQKALVIAHN NIEMAKNILR
910
EFVSISSPAH VAT