P22681 (CBL_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
E3 ubiquitin-protein ligase CBL
EC=6.3.2.-

Alternative name(s):
Casitas B-lineage lymphoma proto-oncogene
Proto-oncogene c-Cbl
RING finger protein 55
Signal transduction protein CBL

Gene names

Name:	CBL
Synonyms:	CBL2, RNF55

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	906 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Adapter protein that functions as a negative regulator of many signaling pathways that are triggered by activation of cell surface receptors. Acts as an E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their degradation by the proteasome. Recognizes activated receptor tyrosine kinases, including KIT, FLT1, FGFR1, FGFR2, PDGFRA, PDGFRB, EGFR, CSF1R, EPHA8 and KDR and terminates signaling. Recognizes membrane-bound HCK and other kinases of the SRC family and mediates their ubiquitination and degradation. Participates in signal transduction in hematopoietic cells. Plays an important role in the regulation of osteoblast differentiation and apoptosis. Essential for osteoclastic bone resorption. The Tyr-731 phosphorylated form induces the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function. Ref.5 Ref.12 Ref.25 Ref.26 Ref.32 Ref.35 Ref.38 Ref.44
Pathway	Protein modification; protein ubiquitination.
Subunit structure	Interacts (phosphorylated at Tyr-731) with PIK3R1. Associates with NCK via its SH3 domain. The phosphorylated C-terminus interacts with CD2AP via its second SH3 domain. Binds to UBE2L3. Interacts with adapters SLA, SLA2 and with the phosphorylated C-terminus of SH2B2. Interacts with EGFR, SYK and ZAP70 via the highly conserved Cbl-N region. Also interacts with SORBS1 and INPPL1/SHIP2. Interacts with phosphorylated LAT2. May interact with CBLB By similarity. Interacts with ALK, AXL, BLK, FGR and FGFR2. Interacts with CSF1R, EPHB1, FLT1, KDR, PDGFRA and PDGFRB; regulates receptor degradation through ubiquitination. Interacts with HCK and LYN. Interacts with TEK/TIE2 (tyrosine phosphorylated). Ref.4 Ref.6 Ref.7 Ref.8 Ref.10 Ref.11 Ref.12 Ref.13 Ref.14 Ref.15 Ref.16 Ref.17 Ref.18 Ref.19 Ref.20 Ref.26 Ref.27 Ref.28 Ref.33 Ref.34 Ref.35 Ref.37 Ref.38 Ref.39 Ref.41 Ref.44
Subcellular location	Cytoplasm. Cell membrane. Note: Colocalizes with FGFR2 in lipid rafts at the cell membrane. Ref.12 Ref.35
Domain	The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme. The N-terminus is composed of the phosphotyrosine binding (PTB) domain, a short linker region and the RING-type zinc finger. The PTB domain, which is also called TKB (tyrosine kinase binding) domain, is composed of three different subdomains: a four-helix bundle (4H), a calcium-binding EF hand and a divergent SH2 domain.
Post-translational modification	Phosphorylated on tyrosine residues by ALK, EGFR, SYK, FYN and ZAP70 By similarity. Phosphorylated on tyrosine residues in response to FLT1 and KIT signaling. Phosphorylated on tyrosine residues by INSR and FGR. Phosphorylated on several tyrosine residues by constitutively activated FGFR3. Not phosphorylated at Tyr-731 by FGFR3. Phosphorylated on tyrosine residues by activated CSF1R, PDGFRA and PDGFRB. Phosphorylated on tyrosine residues by HCK. Ref.4 Ref.7 Ref.9 Ref.11 Ref.13 Ref.19 Ref.24 Ref.25 Ref.26 Ref.27 Ref.32 Ref.37 Ref.41 Ubiquitinated, leading to its degradation via the proteasome. Ref.12 Ref.45
Involvement in disease	Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia (NSLL) [MIM:613563]: A syndrome characterized by a phenotype reminiscent of Noonan syndrome. Clinical features are highly variable, including facial dysmorphism, short neck, developmental delay, hyperextensible joints and thorax abnormalities with widely spaced nipples. The facial features consist of triangular face with hypertelorism, large low-set ears, ptosis, and flat nasal bridge. Some patients manifest cardiac defects. Some have an increased risk for certain malignancies, particularly juvenile myelomonocytic leukemia. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.48
Miscellaneous	This protein has one functional calcium-binding site.
Sequence similarities	Contains 1 Cbl-PTB (Cbl-type phosphotyrosine-binding) domain. Contains 1 RING-type zinc finger. Contains 1 UBA domain.

Ontologies

Keywords
Biological process	Ubl conjugation pathway
Cellular component	Cell membrane Cytoplasm Membrane
Coding sequence diversity	Polymorphism
Disease	Disease mutation Proto-oncogene
Domain	Repeat Zinc-finger
Ligand	Calcium Metal-binding Zinc
Molecular function	Ligase
PTM	Acetylation Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	epidermal growth factor receptor signaling pathway Traceable author statement PubMed 15465819. Source: HGNC fibroblast growth factor receptor signaling pathway Traceable author statement. Source: Reactome negative regulation of apoptotic process Inferred from mutant phenotype PubMed 18070883. Source: UniProtKB negative regulation of epidermal growth factor receptor signaling pathway Traceable author statement. Source: Reactome positive regulation of phosphatidylinositol 3-kinase cascade Inferred from mutant phenotype PubMed 17003487. Source: BHF-UCL positive regulation of receptor-mediated endocytosis Traceable author statement PubMed 15465819. Source: HGNC
Cellular_component	cytosol Traceable author statement. Source: Reactome flotillin complex Inferred from electronic annotation. Source: Compara nucleus Inferred from electronic annotation. Source: InterPro plasma membrane Inferred from direct assay PubMed 15465819. Source: HGNC
Molecular_function	calcium ion binding Inferred from electronic annotation. Source: InterPro sequence-specific DNA binding transcription factor activity Traceable author statement Ref.1. Source: ProtInc signal transducer activity Inferred from electronic annotation. Source: InterPro ubiquitin-protein ligase activity Traceable author statement PubMed 15465819. Source: HGNC zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
EGFR	P00533	4	EBI-518228,EBI-297353
F2RL1	P55085	3	EBI-518228,EBI-4303189
GRB2	P62993	4	EBI-518228,EBI-401755
SH3KBP1	Q96B97	6	EBI-518228,EBI-346595

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 906

906

E3 ubiquitin-protein ligase CBL

PRO_0000055858

Regions

Domain

47 – 351

305

Cbl-PTB

Domain

856 – 895

40

UBA

Calcium binding

227 – 240

14

Ref.46

Zinc finger

381 – 420

40

RING-type

Region

1 – 357

357

Sufficient for interaction with EPHB1

Region

47 – 175

129

4H

Region

176 – 248

73

EF-hand-like

Region

249 – 351

103

SH2-like

Region

352 – 380

29

Linker

Region

648 – 906

259

Interaction with CD2AP

Compositional bias

357 – 476

120

Asp/Glu-rich (acidic)

Compositional bias

477 – 688

212

Pro-rich

Compositional bias

689 – 834

146

Asp/Glu-rich (acidic)

Sites

Binding site

294

1

Phosphotyrosine By similarity

Amino acid modifications

Modified residue

141

1

Phosphotyrosine

Modified residue

197

1

N6-acetyllysine

Modified residue

371

1

Phosphotyrosine; by INSR Ref.19

Modified residue

452

1

Phosphoserine Ref.40

Modified residue

455

1

Phosphotyrosine

Modified residue

552

1

Phosphotyrosine

Modified residue

667

1

Phosphoserine

Modified residue

668

1

Phosphoserine By similarity

Modified residue

669

1

Phosphoserine

Modified residue

674

1

Phosphotyrosine

Modified residue

675

1

Phosphoserine

Modified residue

700

1

Phosphotyrosine; by ABL1 Ref.19 Ref.24

Modified residue

731

1

Phosphotyrosine; by SRC Ref.25

Modified residue

774

1

Phosphotyrosine Ref.19

Modified residue

900

1

Phosphoserine Ref.31

Natural variations

Natural variant

367

1

Q → P in NSLL; causes impaired CBL-mediated degradation of cell-surface receptors in a dominant-negative fashion. Ref.48

VAR_064332

Natural variant

382

1

K → E in NSLL; causes impaired CBL-mediated degradation of cell-surface receptors in a dominant-negative fashion. Ref.48

VAR_064333

Natural variant

390

1

D → Y in NSLL; causes impaired CBL-mediated degradation of cell-surface receptors in a dominant-negative fashion. Ref.48

VAR_064334

Natural variant

420

1

R → Q in NSLL; causes impaired CBL-mediated degradation of cell-surface receptors in a dominant-negative fashion as well as constitutive ERK phosphorylation. Ref.48

VAR_064335

Natural variant

620

1

L → F.
Corresponds to variant rs2227988 [ dbSNP | Ensembl ].

VAR_057211

Natural variant

782

1

P → L.
Corresponds to variant rs2229073 [ dbSNP | Ensembl ].

VAR_057212

Natural variant

904

1

V → I.
Corresponds to variant rs17122769 [ dbSNP | Ensembl ].

VAR_057213

Experimental info

Mutagenesis

80

1

S → D: Abolishes interaction with ZAP70. Ref.46

Mutagenesis

82

1

P → A: Abolishes interaction with ZAP70. Ref.46

Mutagenesis

229

1

D → Q: Abolishes interaction with ZAP70. Ref.46

Mutagenesis

240

1

E → S: Abolishes interaction with ZAP70. Ref.46

Mutagenesis

294

1

R → K: Abolishes interaction with ZAP70. Ref.46

Mutagenesis

306

1

G → E: Abolishes interaction with ZAP70 and EPHB1, but does not affect interaction with SLA. Ref.16 Ref.46

Mutagenesis

371

1

Y → F: Strongly reduces tyrosine phosphorylation by INSR; when associated with F-700 and F-774. Ref.19

Mutagenesis

381

1

C → A: Loss of ubiquitin ligase activity. Ref.12

Mutagenesis

700

1

Y → F: Strongly reduces tyrosine phosphorylation by INSR; when associated with F-371 and F-774. Ref.19

Mutagenesis

731

1

Y → F: No effect on tyrosine phosphorylation by INSR. Loss of phosphorylation by SRC. Inhibition of bone resorption. Abolishes interaction with PIK3R1. Ref.19 Ref.25

Mutagenesis

774

1

Y → F: Strongly reduces tyrosine phosphorylation by INSR; when associated with F-371 and F-700. Ref.19

Sequence conflict

15

1

S → T in CAA40393. Ref.1

Secondary structure

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906

Helix Strand Turn

Details...

Helix

53 – 70

18

Helix

73 – 75

3

Beta strand

79 – 82

4

Helix

84 – 101

18

Turn

102 – 104

3

Helix

106 – 111

6

Helix

113 – 136

24

Helix

137 – 141

5

Helix

146 – 168

23

Helix

170 – 172

3

Helix

176 – 178

3

Helix

184 – 194

11

Beta strand

198 – 201

4

Helix

202 – 212

11

Helix

218 – 228

11

Beta strand

233 – 237

5

Helix

238 – 247

10

Helix

251 – 253

3

Helix

254 – 261

8

Turn

262 – 264

3

Beta strand

268 – 271

4

Helix

274 – 281

8

Helix

282 – 284

3

Beta strand

290 – 295

6

Beta strand

297 – 299

3

Beta strand

302 – 308

7

Turn

310 – 312

3

Beta strand

314 – 317

4

Beta strand

320 – 322

3

Helix

324 – 333

10

Turn

350 – 353

4

Beta strand

354 – 356

3

Beta strand

360 – 362

3

Helix

365 – 373

9

Turn

374 – 376

3

Beta strand

377 – 380

4

Turn

382 – 384

3

Beta strand

385 – 388

4

Beta strand

391 – 394

4

Beta strand

398 – 400

3

Helix

402 – 411

10

Turn

417 – 419

3

Beta strand

425 – 428

4

Beta strand

430 – 432

3

Helix

856 – 866

11

Helix

871 – 880

10

Turn

881 – 883

3

Helix

885 – 895

11

Sequences

	Sequence		Length	Mass (Da)
	P22681 [UniParc]. Last modified July 7, 2009. Version 2. Checksum: 1AA6BF67377322CA	FASTA	906	99,633
	10 20 30 40 50 60 MAGNVKKSSG AGGGSGSGGS GSGGLIGLMK DAFQPHHHHH HHLSPHPPGT VDKKMVEKCW 70 80 90 100 110 120 KLMDKVVRLC QNPKLALKNS PPYILDLLPD TYQHLRTILS RYEGKMETLG ENEYFRVFME 130 140 150 160 170 180 NLMKKTKQTI SLFKEGKERM YEENSQPRRN LTKLSLIFSH MLAELKGIFP SGLFQGDTFR 190 200 210 220 230 240 ITKADAAEFW RKAFGEKTIV PWKSFRQALH EVHPISSGLE AMALKSTIDL TCNDYISVFE 250 260 270 280 290 300 FDIFTRLFQP WSSLLRNWNS LAVTHPGYMA FLTYDEVKAR LQKFIHKPGS YIFRLSCTRL 310 320 330 340 350 360 GQWAIGYVTA DGNILQTIPH NKPLFQALID GFREGFYLFP DGRNQNPDLT GLCEPTPQDH 370 380 390 400 410 420 IKVTQEQYEL YCEMGSTFQL CKICAENDKD VKIEPCGHLM CTSCLTSWQE SEGQGCPFCR 430 440 450 460 470 480 CEIKGTEPIV VDPFDPRGSG SLLRQGAEGA PSPNYDDDDD ERADDTLFMM KELAGAKVER 490 500 510 520 530 540 PPSPFSMAPQ ASLPPVPPRL DLLPQRVCVP SSASALGTAS KAASGSLHKD KPLPVPPTLR 550 560 570 580 590 600 DLPPPPPPDR PYSVGAESRP QRRPLPCTPG DCPSRDKLPP VPSSRLGDSW LPRPIPKVPV 610 620 630 640 650 660 SAPSSSDPWT GRELTNRHSL PFSLPSQMEP RPDVPRLGST FSLDTSMSMN SSPLVGPECD 670 680 690 700 710 720 HPKIKPSSSA NAIYSLAARP LPVPKLPPGE QCEGEEDTEY MTPSSRPLRP LDTSQSSRAC 730 740 750 760 770 780 DCDQQIDSCT YEAMYNIQSQ APSITESSTF GEGNLAAAHA NTGPEESENE DDGYDVPKPP 790 800 810 820 830 840 VPAVLARRTL SDISNASSSF GWLSLDGDPT TNVTEGSQVP ERPPKPFPRR INSERKAGSC 850 860 870 880 890 900 QQGSGPAASA ATASPQLSSE IENLMSQGYS YQDIQKALVI AQNNIEMAKN ILREFVSISS PAHVAT

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The sequences of the human and mouse c-cbl proto-oncogenes show v-cbl was generated by a large truncation encompassing a proline-rich domain and a leucine zipper-like motif." Blake T.J., Shapiro M., Morse H.C. III, Langdon W.Y. Oncogene 6:653-657(1991) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Human chromosome 11 DNA sequence and analysis including novel gene identification." Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G. , Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S., Sakaki Y. Nature 440:497-500(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[4]	"The proto-oncogene p120(Cbl) is a downstream substrate of the Hck protein-tyrosine kinase." Howlett C.J., Bisson S.A., Resek M.E., Tigley A.W., Robbins S.M. Biochem. Biophys. Res. Commun. 257:129-138(1999) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION BY HCK, INTERACTION WITH HCK.
[5]	"The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase." Joazeiro C.A., Wing S.S., Huang H.-K., Leverson J.D., Hunter T., Liu Y.-C. Science 286:309-312(1999) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[6]	"The protein product of the c-cbl protooncogene is the 120-kDa tyrosine-phosphorylated protein in Jurkat cells activated via the T cell antigen receptor." Donovan J.A., Wange R.L., Langdon W.Y., Samelson L.E. J. Biol. Chem. 269:22921-22924(1994) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH BLK.
[7]	"Tyrosine phosphorylation of the c-cbl proto-oncogene protein product and association with epidermal growth factor (EGF) receptor upon EGF stimulation." Galisteo M.L., Dikic I., Batzer A.G., Langdon W.Y., Schlessinger J. J. Biol. Chem. 270:20242-20245(1995) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION BY EGFR, INTERACTION WITH EGFR.
[8]	"The Cbl phosphotyrosine-binding domain selects a D(N/D)XpY motif and binds to the Tyr292 negative regulatory phosphorylation site of ZAP-70." Lupher M.L. Jr., Songyang Z., Shoelson S.E., Cantley L.C., Band H. J. Biol. Chem. 272:33140-33144(1997) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH ZAP70.
[9]	"Coordinated regulation of the tyrosine phosphorylation of Cbl by Fyn and Syk tyrosine kinases." Deckert M., Elly C., Altman A., Liu Y.C. J. Biol. Chem. 273:8867-8874(1998) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION BY SYK AND FYN.
[10]	"Non-T cell activation linker (NTAL): a transmembrane adaptor protein involved in immunoreceptor signaling." Brdicka T., Imrich M., Angelisova P., Brdickova N., Horvath O., Spicka J., Hilgert I., Luskova P., Draber P., Novak P., Engels N., Wienands J., Simeoni L., Oesterreicher J., Aguado E., Malissen M., Schraven B., Horejsi V. J. Exp. Med. 196:1617-1626(2002) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH LAT2.
[11]	"C-Cbl binds the CSF-1 receptor at tyrosine 973, a novel phosphorylation site in the receptor's carboxy-terminus." Wilhelmsen K., Burkhalter S., van der Geer P. Oncogene 21:1079-1089(2002) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH CSF1R, PHOSPHORYLATION.
[12]	"Membrane-anchored Cbl suppresses Hck protein-tyrosine kinase mediated cellular transformation." Howlett C.J., Robbins S.M. Oncogene 21:1707-1716(2002) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, UBIQUITINATION, MUTAGENESIS OF CYS-381, INTERACTION WITH HCK.
[13]	"Fgr but not Syk tyrosine kinase is a target for beta 2 integrin-induced c-Cbl-mediated ubiquitination in adherent human neutrophils." Melander F., Andersson T., Dib K. Biochem. J. 370:687-694(2003) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH FGR, PHOSPHORYLATION BY FGR.
[14]	"APS, an adaptor protein containing pleckstrin homology (PH) and Src homology-2 (SH2) domains inhibits the JAK-STAT pathway in collaboration with c-Cbl." Wakioka T., Sasaki A., Mitsui K., Yokouchi M., Inoue A., Komiya S., Yoshimura A. Leukemia 13:760-767(1999) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH SH2B2.
[15]	"APS, an adaptor protein containing PH and SH2 domains, is associated with the PDGF receptor and c-Cbl and inhibits PDGF-induced mitogenesis." Yokouchi M., Wakioka T., Sakamoto H., Yasukawa H., Ohtsuka S., Sasaki A., Ohtsubo M., Valius M., Inoue A., Komiya S., Yoshimura A. Oncogene 18:759-767(1999) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH SH2B2.
[16]	"SLAP, a dimeric adapter protein, plays a functional role in T cell receptor signaling." Tang J., Sawasdikosol S., Chang J.-H., Burakoff S.J. Proc. Natl. Acad. Sci. U.S.A. 96:9775-9780(1999) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH SLA AND ZAP70, MUTAGENESIS OF GLY-306.
[17]	"Functional cloning of Src-like adapter protein-2 (SLAP-2), a novel inhibitor of antigen receptor signaling." Holland S.J., Liao X.C., Mendenhall M.K., Zhou X., Pardo J., Chu P., Spencer C., Fu A.C., Sheng N., Yu P., Pali E., Nagin A., Shen M., Yu S., Chan E., Wu X., Li C., Woisetschlager M. , Aversa G., Kolbinger F., Bennett M.K., Molineaux S., Luo Y., Payan D.G., Mancebo H.S.Y., Wu J. J. Exp. Med. 194:1263-1276(2001) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH SLA2.
[18]	"The adapter type protein CMS/CD2AP binds to the proto-oncogenic protein c-Cbl through a tyrosine phosphorylation-regulated Src homology 3 domain interaction." Kirsch K.H., Georgescu M.M., Shishido T., Langdon W.Y., Birge R.B., Hanafusa H. J. Biol. Chem. 276:4957-4963(2001) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH CD2AP.
[19]	"APS facilitates c-Cbl tyrosine phosphorylation and GLUT4 translocation in response to insulin in 3T3-L1 adipocytes." Liu J., Kimura A., Baumann C.A., Saltiel A.R. Mol. Cell. Biol. 22:3599-3609(2002) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH SH2B2, MUTAGENESIS OF TYR-371; TYR-700; TYR-731 AND TYR-774, PHOSPHORYLATION AT TYR-371; TYR-700 AND TYR-774.
[20]	"The c-Cbl-associated protein and c-Cbl are two new partners of the SH2-containing inositol polyphosphate 5-phosphatase SHIP2." Vandenbroere I., Paternotte N., Dumont J.E., Erneux C., Pirson I. Biochem. Biophys. Res. Commun. 300:494-500(2003) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH INPPL1.
[21]	"Profiling of tyrosine phosphorylation pathways in human cells using mass spectrometry." Salomon A.R., Ficarro S.B., Brill L.M., Brinker A., Phung Q.T., Ericson C., Sauer K., Brock A., Horn D.M., Schultz P.G., Peters E.C. Proc. Natl. Acad. Sci. U.S.A. 100:443-448(2003) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[22]	"Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry." Brill L.M., Salomon A.R., Ficarro S.B., Mukherji M., Stettler-Gill M., Peters E.C. Anal. Chem. 76:2763-2772(2004) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Leukemic T-cell.
[23]	"Signal transduction via the stem cell factor receptor/c-Kit." Ronnstrand L. Cell. Mol. Life Sci. 61:2535-2548(2004) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON ROLE IN KIT SIGNALING AND KIT DEGRADATION.
[24]	"Catalytic domains of tyrosine kinases determine the phosphorylation sites within c-Cbl." Grossmann A.H., Kolibaba K.S., Willis S.G., Corbin A.S., Langdon W.S., Deininger M.W., Druker B.J. FEBS Lett. 577:555-562(2004) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT TYR-700.
[25]	"Src kinase activity is essential for osteoclast function." Miyazaki T., Sanjay A., Neff L., Tanaka S., Horne W.C., Baron R. J. Biol. Chem. 279:17660-17666(2004) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, PHOSPHORYLATION AT TYR-731, MUTAGENESIS OF TYR-731.
[26]	"Cbl-mediated degradation of Lyn and Fyn induced by constitutive fibroblast growth factor receptor-2 activation supports osteoblast differentiation." Kaabeche K., Lemonnier J., Le Mee S., Caverzasio J., Marie P.J. J. Biol. Chem. 279:36259-36267(2004) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, PHOSPHORYLATION, INTERACTION WITH FGFR2; LYN AND FYN.
[27]	"ALK receptor tyrosine kinase promotes cell growth and neurite outgrowth." Motegi A., Fujimoto J., Kotani M., Sakuraba H., Yamamoto T. J. Cell Sci. 117:3319-3329(2004) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH ALK, PHOSPHORYLATION BY ALK.
[28]	"Effects of Gas6 and hydrogen peroxide in Axl ubiquitination and downregulation." Valverde P. Biochem. Biophys. Res. Commun. 333:180-185(2005) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH AXL.
[29]	"Signaling by Kit protein-tyrosine kinase--the stem cell factor receptor." Roskoski R. Jr. Biochem. Biophys. Res. Commun. 337:1-13(2005) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON ROLE IN KIT SIGNALING AND KIT DEGRADATION.
[30]	"Immunoaffinity profiling of tyrosine phosphorylation in cancer cells." Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H., Zha X.-M., Polakiewicz R.D., Comb M.J. Nat. Biotechnol. 23:94-101(2005) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[31]	"A probability-based approach for high-throughput protein phosphorylation analysis and site localization." Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P. Nat. Biotechnol. 24:1285-1292(2006) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-900, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[32]	"The localization of FGFR3 mutations causing thanatophoric dysplasia type I differentially affects phosphorylation, processing and ubiquitylation of the receptor." Bonaventure J., Horne W.C., Baron R. FEBS J. 274:3078-3093(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, PHOSPHORYLATION.
[33]	"Binding of Cbl to a phospholipase Cgamma1-docking site on platelet-derived growth factor receptor beta provides a dual mechanism of negative regulation." Reddi A.L., Ying G., Duan L., Chen G., Dimri M., Douillard P., Druker B.J., Naramura M., Band V., Band H. J. Biol. Chem. 282:29336-29347(2007) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH PDGFRB.
[34]	"Lyn regulates BCR-ABL and Gab2 tyrosine phosphorylation and c-Cbl protein stability in imatinib-resistant chronic myelogenous leukemia cells." Wu J., Meng F., Lu H., Kong L., Bornmann W., Peng Z., Talpaz M., Donato N.J. Blood 111:3821-3829(2008) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH LYN.
[35]	"FGFR2-Cbl interaction in lipid rafts triggers attenuation of PI3K/Akt signaling and osteoblast survival." Dufour C., Guenou H., Kaabeche K., Bouvard D., Sanjay A., Marie P.J. Bone 42:1032-1039(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH FGFR2, SUBCELLULAR LOCATION.
[36]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Cervix carcinoma.
[37]	"Ligand binding induces Cbl-dependent EphB1 receptor degradation through the lysosomal pathway." Fasen K., Cerretti D.P., Huynh-Do U. Traffic 9:251-266(2008) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH EPHB1, PHOSPHORYLATION.
[38]	"Angiopoietin-1-induced ubiquitylation of Tie2 by c-Cbl is required for internalization and degradation." Wehrle C., Van Slyke P., Dumont D.J. Biochem. J. 423:375-380(2009) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH TEK/TIE2, FUNCTION.
[39]	"An unbiased screen identifies DEP-1 tumor suppressor as a phosphatase controlling EGFR endocytosis." Tarcic G., Boguslavsky S.K., Wakim J., Kiuchi T., Liu A., Reinitz F., Nathanson D., Takahashi T., Mischel P.S., Ng T., Yarden Y. Curr. Biol. 19:1788-1798(2009) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH EGFR.
[40]	"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions." Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K. Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-452, MASS SPECTROMETRY. Tissue: Leukemic T-cell.
[41]	"Mutation of tyrosine residue 857 in the PDGF beta-receptor affects cell proliferation but not migration." Wardega P., Heldin C.H., Lennartsson J. Cell. Signal. 22:1363-1368(2010) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH PDGFRB, PHOSPHORYLATION.
[42]	"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis." Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M. Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Cervix carcinoma.
[43]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[44]	"The Casitas B lineage lymphoma (Cbl) mutant G306E enhances osteogenic differentiation in human mesenchymal stromal cells in part by decreased Cbl-mediated platelet-derived growth factor receptor alpha and fibroblast growth factor receptor 2 ubiquitination." Severe N., Miraoui H., Marie P.J. J. Biol. Chem. 286:24443-24450(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH FGFR2.
[45]	"Fibroblast growth factor signalling: from development to cancer." Turner N., Grose R. Nat. Rev. Cancer 10:116-129(2010) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION IN FGF SIGNALING, UBIQUITINATION OF FGFR1.
[46]	"Structure of the amino-terminal domain of Cbl complexed to its binding site on ZAP-70 kinase." Meng W., Sawasdikosol S., Burakoff S.J., Eck M.J. Nature 398:84-90(1999) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 47-350 IN COMPLEX WITH ZAP70 PEPTIDE AND CALCIUM IONS, CALCIUM-BINDING SITE, MUTAGENESIS OF SER-80; PRO-82; ASP-229; GLU-240; ARG-294 AND GLY-306.
[47]	"Structure of a c-Cbl-UbcH7 complex: RING domain function in ubiquitin-protein ligases." Zheng N., Wang P., Jeffrey P.D., Pavletich N.P. Cell 102:533-539(2000) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 47-434 IN COMPLEX WITH ZAP70 AND UBE2L3.
[48]	"Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype." Martinelli S., De Luca A., Stellacci E., Rossi C., Checquolo S., Lepri F., Caputo V., Silvano M., Buscherini F., Consoli F., Ferrara G., Digilio M.C., Cavaliere M.L., van Hagen J.M., Zampino G., van der Burgt I., Ferrero G.B., Mazzanti L. , Screpanti I., Yntema H.G., Nillesen W.M., Savarirayan R., Zenker M., Dallapiccola B., Gelb B.D., Tartaglia M. Am. J. Hum. Genet. 87:250-257(2010) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS NSLL PRO-367; GLU-382; TYR-390 AND GLN-420, CHARACTERIZATION OF VARIANTS NSLL PRO-367; GLU-382; TYR-390 AND GLN-420.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

X57110 mRNA. Translation: CAA40393.1.
AP002956 Genomic DNA. No translation available.
BC132733 mRNA. Translation: AAI32734.1.
BC136463 mRNA. Translation: AAI36464.1.

IPI

IPI00027269.

PIR

A43817.

RefSeq

NP_005179.2. NM_005188.3.

UniGene

Hs.504096.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1B47	X-ray	2.20	A/B/C	47-350	[»]
1FBV	X-ray	2.90	A	47-434	[»]
1YVH	X-ray	2.05	A	25-351	[»]
2CBL	X-ray	2.10	A	47-351	[»]
2JUJ	NMR	-	A	851-906	[»]
2K4D	NMR	-	A	358-437	[»]
2OO9	X-ray	2.10	A/B/C	856-895	[»]
2Y1M	X-ray	2.67	A/B/C/D/E/F	47-435	[»]
2Y1N	X-ray	2.00	A/C	47-435	[»]
3BUM	X-ray	2.00	B	25-351	[»]
3BUN	X-ray	2.00	B	25-351	[»]
3BUO	X-ray	2.60	B/D	25-351	[»]
3BUW	X-ray	1.45	B/D	25-351	[»]
3BUX	X-ray	1.35	B/D	25-351	[»]
3OB1	X-ray	2.20	B	25-351	[»]
3OB2	X-ray	2.10	B	25-351	[»]
3PLF	X-ray	1.92	B/D	25-351	[»]
4A49	X-ray	2.21	A	354-435	[»]
4A4B	X-ray	2.79	A	47-435	[»]
4A4C	X-ray	2.70	A	47-435	[»]

ProteinModelPortal

P22681.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-189N.

IntAct

P22681. 27 interactions.

MINT

MINT-109040.

STRING

9606.ENSP00000264033.

PTM databases

PhosphoSite

P22681.

Polymorphism databases

DMDM

251757253.

Proteomic databases

PaxDb

P22681.

PRIDE

P22681.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000264033; ENSP00000264033; ENSG00000110395.

GeneID

867.

KEGG

hsa:867.

UCSC

uc001pwe.3. human.

Organism-specific databases

CTD

867.

GeneCards

GC11P119110.

HGNC

HGNC:1541. CBL.

HPA

CAB004350.
HPA027956.

MIM

165360. gene.
613563. phenotype.

neXtProt

NX_P22681.

Orphanet

648. Noonan syndrome.

PharmGKB

PA26115.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG242251.

HOGENOM

HOG000294176.

HOVERGEN

HBG005255.

InParanoid

P22681.

KO

K04707.

OMA

TTNFTEG.

OrthoDB

EOG444KJR.

PhylomeDB

P22681.

Enzyme and pathway databases

Pathway_Interaction_DB

epha_fwdpathway. EPHA forward signaling.
epha2_fwdpathway. EPHA2 forward signaling.
epopathway. EPO signaling pathway.
fcer1pathway. Fc-epsilon receptor I signaling in mast cells.
fgf_pathway. FGF signaling pathway.
ifngpathway. IFN-gamma pathway.
il4_2pathway. IL4-mediated signaling events.
insulin_pathway. Insulin Pathway.
avb3_integrin_pathway. Integrins in angiogenesis.
a4b1_paxdep_pathway. Paxillin-dependent events mediated by a4b1.
a4b1_paxindep_pathway. Paxillin-independent events mediated by a4b1 and a4b7.
pdgfrbpathway. PDGFR-beta signaling pathway.
reelinpathway. Reelin signaling pathway.
met_pathway. Signaling events activated by Hepatocyte Growth Factor Receptor (c-Met).
kitpathway. Signaling events mediated by Stem cell factor receptor (c-Kit).
tcrpathway. TCR signaling in naive CD4+ T cells.
cd8tcrpathway. TCR signaling in naive CD8+ T cells.
vegfr1_pathway. VEGFR1 specific signals.

Reactome

REACT_111102. Signal Transduction.
REACT_116125. Disease.
REACT_6900. Immune System.

UniPathway

UPA00143.

Gene expression databases

Bgee

P22681.

CleanEx

HS_CBL.

Genevestigator

P22681.

GermOnline

ENSG00000110395. Homo sapiens.

Family and domain databases

Gene3D

1.10.238.10. 1 hit.
1.20.930.20. 1 hit.
3.30.40.10. 1 hit.
3.30.505.10. 1 hit.

InterPro

IPR024162. Adaptor_Cbl.
IPR014741. Adaptor_Cbl_EF_hand-like.
IPR003153. Adaptor_Cbl_N_hlx.
IPR014742. Adaptor_Cbl_SH2-like.
IPR024159. Cbl_PTB.
IPR011992. EF-hand-like_dom.
IPR000980. SH2.
IPR009060. UBA-like.
IPR000449. UBA/transl_elong_EF1B_N.
IPR015940. UBA/transl_elong_EF1B_N_euk.
IPR018957. Znf_C3HC4_RING-type.
IPR001841. Znf_RING.
IPR013083. Znf_RING/FYVE/PHD.
IPR017907. Znf_RING_CS.
[Graphical view]

PANTHER

PTHR23007. PTHR23007. 1 hit.

Pfam

PF02262. Cbl_N. 1 hit.
PF02761. Cbl_N2. 1 hit.
PF02762. Cbl_N3. 1 hit.
PF00627. UBA. 1 hit.
PF00097. zf-C3HC4. 1 hit.
[Graphical view]

SMART

SM00184. RING. 1 hit.
SM00165. UBA. 1 hit.
[Graphical view]

SUPFAM

SSF47668. Adaptor_Cbl_N. 1 hit.
SSF46934. UBA_like. 1 hit.

PROSITE

PS51506. CBL_PTB. 1 hit.
PS50030. UBA. 1 hit.
PS00518. ZF_RING_1. 1 hit.
PS50089. ZF_RING_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

P22681.

GenomeRNAi

867.

NextBio

3618.

PMAP-CutDB

P22681.

SOURCE

Search...

Entry information

Entry name

CBL_HUMAN

Accession

Primary (citable) accession number: P22681
Secondary accession number(s): A3KMP8

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 1, 1991
Last sequence update:	July 7, 2009
Last modified:	May 1, 2013
This is version 163 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.