Map Key
Generic Enzyme
Generic kinase
Protein kinase
Lipid kinase
Generic phosphatase
Protein phosphatase
Lipid phosphatase
Generic phospholipase
Generic protease
RAS - superfamily
G beta/gamma
Regulators (GDI, GAP, GEF)
Generic channel
Ligand-gated channel
Voltage-gated channel
Normal process
Pathological process
Positive effect
Negative effect
Unspecified effect
Technical link
Disrupts in disease
Emerges in disease
Enhances in disease
Weakens in disease
Organsim specific interaction

Generic binding protein
Receptor ligand
Cell membrane glycoprotein
Transcription factor
Inorganic ion
Predicted metabolite or user's structure
Generic receptor
Receptors with enzyme activity

Normal process
Pathological process
Covalent modifications
Transcription regulation
MicroRNA binding
Influence on expression
Unspecified interactions
Pharmacological effect
Toxic effect
Group relation
Complex subunit
Similarity reaction
A complex or a group
Organism specific object

Development ERBB-family signaling

Log In to Post A Comment

Development ERBB-family signaling

ERBB-family signaling

The ERBB family of receptor tyrosine kinases consists of four closely relatedmembers: Epidermal growth factor receptor ( EGFR, also known as ERBB1), v-erb-b2erythroblastic leukemia viral oncogene homolog 2, 3 and 4 ( ERBB2, ERBB3,and ERBB4 ). Binding of extracellular growth factor ligands is coupled withintracellular signaling pathways regulating diverse biologic responses, includingproliferation, differentiation, cell motility, and survival [1].

All ERBB receptors, excluding ERBB2, have their specific, partiallyoverlapping, ligands. EGF, Amphiregulin, Transforming growth factor alpha( TGF-alpha ) bind to EGFR only; Betacellulin, Heparin bindingEGF-like growth factor (HB-EGF ) and Epiregulin both bind EGFR andERBB4; the Neuregulins 1 and 2 ( NRG-1 and NRG-2 ) bind bothERBB3 and ERBB4; and NRG-3 and NRG-4 bind only ERBB4[1], [2], [3].

No known ligand binds ERBB2. ERBB2 is a unique member of theERBB family in that it does not bind any of the known ligands with high affinity,but it is the preferred heterodimeric partner for other ERBB - receptors [1].

Ligand binding induces homo- or heterodimerization of ERBB s, resulting inreceptor transphosphorylation, which significantly enhances kinase activity.

Activation of receptors stimulates three generic cascades: Phosphoinositide-3-kinase (PI3K ) / V-akt murine thymoma viral oncogene homolog 1 (AKT(PKB)).signaling cascade, V-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-Ras)-dependent Mitogen-activated protein kinase 3/1 ( ERK1/2 ) kinase cascade andNuclear factor of kappa B ( NF-kB ) activation pathway.

ERBB s recruit p85 regulatory subunit of phosphatidylinositol-3-kinase (PI3K reg class 1A ) either directly (in case of ERBB3 and ERBB4 ) orvia adaptor proteins Growth factor receptor-bound protein 2 ( GRB2 ) and Cas-Br-M(murine) ecotropic retroviral transforming sequence ( c-Cbl ) , in case ofEGFR. Membrane-targeting catalytic subunit of PI3K ( PI3K cat class 1A )becomes active and converts Phosphoinositide 4,5-bisphosphate ( PtdIns(4,5)P2 ) toPhosphatidylinositol 3,4,5-triphosphate ( PtdIns(3,4,5)P3 ), which is a secondmessenger involved in regulation various process [4].

EGFR and ERBB3 stimulate ERK kinase cascade. EGFR andERBB3 recruit Son of sevenless homolog ( SOS ) via adaptor proteinGRB2 and SHC transforming protein ( Shc ) , respectively. SOSis a guanine-nucleotide exchange factor for small GTPases, including H-Ras.H-Ras causes cascade of phosphorylation reactions that activate Transcriptionfactors ELK1 member of ETS oncogene family ( Elk-1 ), V-fos FBJ murineosteosarcoma viral oncogene homolog ( c-Fos ), and V-myc myelocytomatosis viraloncogene homolog ( c-Myc ) [5].

Adaptor protein Growth factor receptor-bound protein 7 ( GRB7 ) is involved inERBB-stimulated NF-kB pathway. GRB7 and Mitogen-activated protein kinase kinasekinase 14 ( NIK ) could be simultaneously recruited into signaling complexes ofall three receptors: EGFR, ERBB3, and ERBB4 [6].NIK phosphorylates and activates Catalytic subunits of the I-kappa-B kinase (IKK (cat) ) that regulates the activity of the Nuclear factor-kappa B (NF-kB ) transcription factor. When bound to its cytosolic inhibitor Nuclear factorof kappa light polypeptide gene enhancer in B-cells inhibitor ( I-kB ), NF-kB is inactive as a transcription factor. Upon phosphorylation of I-kB byIKK, the inhibitor is degraded, allowing NF-kB to move to the nucleus andactivate the transcription of antiapoptotic proteins [7].