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FLASH GENE

Symbol

CBL

contributors: mct/npt - updated : 21-08-2015

HGNC name	Cas-Br-M (murine) ecotropic retroviral transforming sequence
HGNC id	1541

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	CBLS CBL syndrome NS7 Noonan syndrome 7
Location	11q23.3      Physical location : 119.076.989 - 119.178.858
Synonym name	oncogene CBL2
	Casitas B-lineage lymphoma proto-oncogene
	proto-oncogene c-CBL
	RING finger protein 55
	signal transduction protein CBL
	fragile site, folic acid type, rare, fra(11)(q23.3)
Synonym symbol(s)	C-CBL, CBL2, RNF55, FRA11B, NSLL
EC.number	6.3.2.-

DNA

TYPE	virus associated
STRUCTURE	101.87 kb     16 Exon(s)

10 Kb 5' upstream gene genomic sequence study

text structure

CGG trinucleotide repeat

MAPPING

cloned

Y

linked

N

status

confirmed

Map	see BALMCR

RNA

TRANSCRIPTS	type	untranslated

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_005188 16 - 11242 NP_005179 120 906 - 2009 19620960

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Lymphoid/Immune thymus       highly Homo sapiens

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Lymphoid

cells

System Cell Pubmed Species Stage Rna symbol Blood/Hematopoietic mature hematopoietic

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a variant SH2 domain, with tyrosine kinase binding (TKB)
	a potential nuclear localization signal (NLS)
	a RING finger domain
	C-terminus with an extensive proline-rich region containing a number of putative SH3-binding motifs, and is followed by multiple SH2-binding tyrosine phosphorylation sites and a ubiquitin-associated (UBA) domain overlapping with a leucine zipper (LZ) motif involved in ubiquitin binding and protein dimerization, respectively
	C-terminal region plays a crucial role in the temporal and spatial control of HTR2A recycling

HOMOLOGY

Homologene

FAMILY

CATEGORY

tumor suppressor

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,cytosolic
	intracellular,nucleus
text	phosphorylated CBL recruited to the insulin receptor by CAP (SORBS1) and translocated to cholesterol enriched microdomains (lipid rafts)

basic FUNCTION	acting as a RING-type E3-dependent ubiquitin protein ligase, binding and stimulating the ubiquitination of PDGFRs, EGFR, CSF1R, also interacting with signal transduction molecules, key mediator of HCK (hematopoietic cell kinase) induced signaling in hematopoietic cells
	involvement of a CBL/PTPN11complex in ubiquitination and lysosomal degradation of IL6ST upon IL6 stimulation
	critical regulator of the functional responses of memory T cell subsets
	both CBL and CBLB perform regulatory functions in osteoclasts that are unique to one or the other protein (i.e., functions that cannot be compensated by the other homolog)
	may have a role in deregulating a key pathway in JMML (juvenile myelomonocytic leukemia)
	negatively regulates JNK activation and cell death
	E3 ubiquitin ligase that negatively regulates signal transduction of tyrosine kinases
	negatively regulate intracellular signaling downstream of receptor tyrosine kinases (RTKs), but it also contributes to signal traffic through its adaptor function
	angiogenic suppressor protein where upon activation it uniquely modulates PLCG1 activation by ubiquitination and subsequently inhibits VEGF-driven angiogenesis
	has a crucial, RING-domain-dependent role in regulating dendritic cell maturation, probably by facilitating the regulatory function of NFKB1
	CBL and particularly its phosphorylated residue Y731 plays an important role in platelet outside-in signaling contributing to platelet-spreading and clot retraction
	plays a critical role TCR signaling downregulation during thymocyte development
	regulates the osteoblastic differentiation program in mesenchymal cells by controlling CBL-mediated STAT5A degradation and activity
	LCK, which plays a unique role in enforcing MHC restriction, is essential for thymic development in presence or absence of CBL, ensuring MHC restriction of T cells derived from either pathway
	recycling regulator ARHGEF6 and the degradation factor CBL closely cooperate in the regulation of EGFR trafficking (pMID: 26177020)

CELLULAR PROCESS	cell life, proliferation/growth
	protein, degradation
	protein, ubiquitin dependent proteolysis

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

signal transduction

insulin signaling pathway

a component

ubiquitination component of a complex with UBE1, UBE3*, UBE2G1, UBE2D1, UBE2E2, UBE2D1

INTERACTION

DNA

RNA

small molecule

protein	recruiting the CRK/GRF2 complex to lipid rafts
	interacting with signal transduction molecules : PD6FRS, EGFR, CSF1R
	binding E2 by its RING domain regulation ZAP70, SYK tyrosine kinases
	negatively regulating LCK
	competition between CBL and ubiquitin binding to SH3KBP1 regulates CBL function and EGFR endocytosis
	interacts with the TEK signalling complex in a stimulation-dependent manner, and that this interaction is required for TEK ubiquitylation, internalization and degradation
	is an angiogenic suppressor protein where upon activation it uniquely modulates PLCG1 activation by ubiquitination and subsequently inhibits VEGFA-driven angiogenesis
	VHL limits EGFR signaling by promoting CBL-independent poly-ubiquitylation of the activated receptor, which likely results in its degradation by proteasome
	CBL activation induced by CTSG was mediated through EGFR transactivation as inhibition of EGFR kinase activity markedly attenuated CBL phosphorylation and focal adhesion protein degradation induced by CTSG
	SH3KBP1 is required for CBL-mediated regulation of BCR signaling and for downstream events such as survival, growth, and differentiation of human B cells
	ubiquitin ligase that physically associates with CD5
	interacts with the transcription factor STAT5A, and STAT5A forms a complex with RUNX2, a master transcription factor controlling osteoblastogenesis
	CBL ubiquitination of PIK3R1 is essential for EPO-induced EPOR endocytosis
	CBLB and CBL increased the protein level and stability of SIRT2 and CBLB and CBL interact with SIRT2
	CBL negatively regulates ARHGEF6-mediated cell migration and invasion and the lack of CBL in the C6 and A172 glioma cells is responsible for their malignant behavior
	SMAD7 interaction with CBL to inhibit the ubiquitination of EGFR
	2008)
	ARHGEF6 interacts with the E3 ubiquitin ligase CBL, an enzyme that attaches ubiquitin to EGFR, thereby labelling this tyrosine kinase receptor for lysosomal degradation

cell & other

REGULATION

activated by

tyrosine-phosphorylated by insulin

Phosphorylated by

PTK6, that phosphorylates and down-regulates E3 ubiquitin ligase CBL, promoting degradation of CBL through PTK6-mediated phosphorylation (PMId: 23352614)

ASSOCIATED DISORDERS

corresponding disease(s)

NS7 , CBLS

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral fusion       with MLL in acute myeloid leukemia (amino-terminal region of MLL to the proline-rich regions and the ubiquitin -associated leucine zipper domain of CBL) tumoral somatic mutation     gain of function in myeloid neoplasms tumoral germinal mutation       associated with juvenile myelomonocytic leukaemia

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cancer bone   increasing CBL expression reduces osteosarcoma cell growth, survival, and metastasis in part through downregulation of RTKs (receptor tyrosine kinase), which supports the potential therapeutic interest of targeting CBL in malignant bone diseases involvin

ANIMAL & CELL MODELS