Preferred Label : Vesicle Transport Pathway;
NCIt related terms : The role of FYVE-finger proteins in vesicle transport;
Alternative definition : BIOCARTA: Eukaryotic cells take up constituents of the extra-cellular environment
and regulate the cell-surface level of membrane proteins via a recycling system of
membrane vesicles called endosomes. When cells are taking up elements from the cell-surface
it is called endocytosis, and when they are delivered to the cell-surface it is called
exocytosis. The transferrin receptor (TfR) is often employed as a model protein for
studying this process. The transferrin receptor mediates uptake of iron by binding
diferrictransferrin (Tf-2Fe ) from the plasma. Endocytosis of the receptor is initiated
by the formation of a clathrin-coated pit in the cell membrane, which subsequently
forms the primary endosome and then fuses with the early endosome. The lumen of an
early endosome has a slightly acidic pH, which enables the ions to be released. The
ions move to the cytosol and the receptor-apotransferrin (Tf) complex is sorted for
recycling back to the cell membrane in recycling endosomes. At the cell surface the
apotransferrin is replaced with diferrictransferrin and the cycle repeats. Whether
an endocytosed protein is recycled or not is determined by a sorting process initiated
in the early endosome. The early endosome is the first organelle along the endo-lysosomal
pathway and it is the major sorting station. Internalized membrane proteins can either
be sorted for recycling from the early endosome by a fast route (e.g., TfR) or make
it to the late endosome and recycle by a slow route (e.g., angiotensin receptor, AT1R)
or be retained in the late endosome and directed to the lysosome for degradation (e.g.,
epidermal growth factor receptor, EGFR). The early endosome has been suggested to
turn into a multi-vesicular late endosome through a maturation process that changes
its biochemical composition and morphology. The late endosome is followed by the lysosome,
which is the terminal organelle on the endocytic pathway and is devoid of recycling
receptors. The lysosome has a very acidic environment and contains proteases. Vesicular
trafficking and proper sorting of internalized proteins require the recruitment of
cytosolic proteins to a specific endosomal membrane in a reversible and regulated
manner. Many proteins become reversibly localized to membranes through interaction
with specific lipid head groups. Phosphatidylinositol 3-phosphate (PI3P) is a minor
PI3K product that is constitutively produced and specifically localize to early endosomes
and several proteins bind specifically to its head group. These proteins all have
a domain called a FYVE-finger which binds to PI3P. It is a cysteine-rich domain reminiscent
of a zinc finger with eight conserved cysteines, which coordinate two Zinc ions, and
several other conserved residues. Two FYVE finger proteins important in vesicle transport
are illustrated in this pathway. The first and most well studied is the early endosomal
autoantigen (EEA1). It is a protein involved in fusion of primary endosomes with early
endosomes. EEA1 is a large coiled-coil protein that contains a C-terminal FYVE-finger
and two domains that bind to the active, GTP-bound form of the early-endosomal GTPase
Rab5. One of these domains is adjacent to the FYVE-finger, whereas the other, a C2H2-type
zinc finger, is found at the N terminus. The C terminus of EEA1, containing one Rab5-binding
domain and the FYVE-finger, is necessary and sufficient for specific targeting of
EEA1 to early endosomes, and the membrane binding requires both PI3K activity and
Rab5:GTP. The relatively low affinities of the C-terminal Rab5-binding domain for
Rab5:GTP and of the FYVE-finger for PI3P secure that under physiological conditions,
EEA1 is only recruited to membranes that contain both of these components and Rab5
is required on both membranes in order for the fusion to take place. The second FYVE
finger protein in this pathway is HRS. It is also present in early endosomal membranes
and is involved in sorting of endocytosed proteins. ...;
NCIt note : The BIOCARTA Definition (ALT_DEFINITION) for this pathway concept was provided by
BioCarta. This property was not created by, nor is it maintained by the NCI Thesaurus
staff. Additionally, BioCarta is no longer updating its pathway data; thus, the BIOCARTA
Definition might be outdated or inaccurate. Please see the Terms and Conditions for
Use at http://www.biocarta.com/.;
Biocarta ID : h_eea1Pathway;
Origin ID : C39056;
UMLS CUI : C1519978;
Semantic type(s)
- has_gene_product_element
- pathway_has_gene_element
