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FLASH GENE

Symbol

EIF4EBP1

contributors: mct/npt - updated : 20-10-2017

HGNC name	eukaryotic translation initiation factor 4E binding protein 1
HGNC id	3288

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains

a C terminal region for phosphorylation and regulation of function, and conserved motif within the flexible C-terminus of the translational regulator EIF4EBP1 is required for tight binding to the mRNA cap-binding protein EIF4E

secondary structure

an alpha helical structure involved in the control of translation initiation

conjugated

PhosphoP , Other

HOMOLOGY

interspecies	homolog to murine Eif4ebp1 (91.5pc)
	homolog to rattus Eif4ebp1 (93.2pc)

intraspecies	paralog to EIF4EBP2
	paralog to EIF4EBP3

Homologene

FAMILY

eIF4E-binding protein family

CATEGORY

regulatory , tumor suppressor

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,cytosolic
	intracellular,nucleus

basic FUNCTION	translational repressor, negatively regulating translation by EIF4E, by preventing its assembly into the EIF4F complex
	acting as a tumor suppressor
	mediates the regulation of protein translation by hormones, growth factors and other stimuli that signal through the MAP kinase and mTORC1 pathway
	EIF4EBP1, EIF4EBP2 regulate the Stress granules (SGs) localization of EIF4E
	is essential for TGFbeta-mediated inhibition of cell proliferation (Azar 2009)
	activated EIF4EBP1 represses tumorigenesis and IGF-I-mediated activation of the eIF4F complex in mesothelioma (Jacobson 2009)
	modifier of cytoplasmic EIF4E relocalization during the heat shock response (Sukarieh 2009)
	EIF4EBP1, beyond its role in translation regulation, can function as a regulator of mitosis via interacting with PLK1, and possibly plays a role in genomic stability maintaining
	EIF4EBP1 is neither a major nor robust physiological substrate of LRRK2 in mammalian cells or brain
	requirement of the EIF4EBP1 and EIF4EBP2 for the synergistic down-regulation of protein synthesis by hypertonic conditions and MTOR inhibition
	has pro-tumorigenic functions as it promotes tumor adaptation to metabolic and genotoxic stress by selectively enhancing or preventing the translation of specific transcripts
	FGF signaling differentially impacts protein synthesis through either stimulation or repression, in a cell-type-dependent manner, with EIF4EBP1 being a key player

CELLULAR PROCESS	cell life, cell death/apoptosis
	protein, translation/synthesis

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

involved in insulin mediated control pathway

a component

assembling with eIF4A, PABPC1, eIF4E, eIF4BP2, eIF4BP3, MNK1 and eIF4G to form the eukaryotic translation initiation complex EIF4FEBP1

INTERACTION

DNA

RNA

small molecule

protein	binding in its non-phosphorylated form to EIF4E
	interacting with RPTOR
	represses translation initiation by binding to eukaryotic initiation factor 4E (EIF4E)
	EIF4E2 interaction with EIF4EBP1 is necessary for this observed impaired signaling to EIF4EBP1 and RPS6KB1
	EIF4EBP1 inhibits cap-dependent translation by binding to the EIF4E translation initiation factor
	activity of EIF4E is under homeostatic control via the regulation of the levels of its repressor protein EIF4EBP1 through ubiquitination
	PPM1G binds to EIF4EBP1 in cells (PPM1G is a novel regulator of cap-dependent protein translation by negatively controlling the phosphorylation of EIF4EBP1)
	MTOR controls mitochondrial activity and biogenesis by selectively promoting translation of nucleus-encoded mitochondria-related mRNAs via inhibition of the eukaryotic translation initiation factor EIF4EBP1, EIF4EBP2
	RPTOR in MTOR complex 1 is believed to recruit EIF4EBP1, facilitating phosphorylation of EIF4EBP1 by the kinase MTOR
	GSPT2 biomarker for hepatocellular carcinoma, influencing cell cycle and phosphoralation status of EIF4EBP1
	MTOR activation inhibits eukaryotic translation initiation factor 4E-binding protein (EIF4EBP1) and activates ribosomal protein S6 kinase 1 (RPS6KB1), both of which stimulate translation
	regulation of EIF4EBP1 in skeletal muscle may serve as an important conduit through which MTOR controls metabolism
	translational control by EIF4EBP1 downstream of MTOR effects the expression of neuroligin 1 and excitatory synaptic transmission in the spinal cord, and thereby contributes to enhanced mechanical nociception
	EIF4EBP1 has tumor suppressor activity by inhibiting EIF4E and, thus, blocking mRNA translation and proliferation
	ability of EIF4E to recognize the cap is prevented by its binding to EIF4E binding protein (EIF4EBP1), which thereby inhibits cap-dependent translation by sequestering EIF4E

cell & other

REGULATION

induced by

SMAD4 through binding to a conserved element in the EIF4EBP1 promoter (Azar 2009)

Other	phosphorylation events govern the proapoptotic potency of EIF4EBP1
	phosphorylated in response to various signals including UV irradiation and insulin signaling, resulting in its dissociation from EIF4E and activation of mRNA translation
	phosphorylated by mTORC1
	phosphorylation inhibited by RhoE (Villalonga 2009)
	phosphorylation of EIF4EBP1 causes its release from EIF4E to allow cap-dependent translation to proceed

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --low   hyperphosphorylated in some cancers tumoral         phosphorylated EIF4EBP1 expression in endometrial cancer correlates with aggressive tumors and prognosis (Castellvi 2009) tumoral     --over   upregulation in eutopic endometrium may be associated with the pathogenesis of endometriosis (Laudanski 2009)

Susceptibility

Variant & Polymorphism

Candidate gene	expression of mTOR and EIF4EBP1 characterize high-grade, high-stage endometrial adenocarcinomas and might be predictive markers of a response to rapamycin (Darb-Esfahani 2009)
Marker
Therapy target
	System Type Disorder Pubmed cancer     for cancer therapy, potentially (small-molecule inhibitors that pharmacologically mimic function) cancer skin   phosphorylated EIF4EBP1 is associated with poor survival in melanoma and effective inhibition of the pathways responsible for EIF4EBP1 phosphorylation should be considered to improve the treatment outcome of metastatic melanoma patients

ANIMAL & CELL MODELS

elevated Eif4ebp1 expression observed in the retina of diabetic rodents is the result of O-GlcNAcylation of Eif4ebp1 within its PEST motif