User:Lnbond92/sandbox
| EpsinR1 | |
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Epsin
[edit]Epsin's are a highly conserved family of endocytic adaptors that function by recognizing ubiquinated cargo on cell surface receptors [1]. They have been implicated in many pathways particularly playing role in the activation of Notch Signaling Pathway which is an essential pathway in embryo development. In general, most vertebrates contain at least two epsin paralogs. The two paralogs, epsin-1 and epsin-2 are members that contribute to the clathrin coated endocytotic machinery and are localized at the plasma membrane [1].
Structure
[edit]Epsin contains various protein domains that aid in function. Starting at the N - terminus is the ENTH domain. ENTH stands for Epsin N - Terminal Homolog. The ENTH domain is approximately 150 amino - acids long and is highly conserved across species [1]. It is comprised of seven α - helices and an eighth helix that is not aligned with the seven helices that make up a superhelical fold [1]. The role of the ENTH domain is to bind phosphatidyl -inositol (4,5) bisphosphate which mediates the recruitment of epsin to the plasma membrane and aid in the formation of clathrin coated pit formation through an invagination of the plasma membrane [2]. Additionally, located toward the C terminus of the ENTH domain are two to three ubiquitin interacting motifs (UIM) which aids in ubiquitin dependent recruitment [1]. Additionally, UIMs provide specificity for the ubiquitinates targets for internalization [2].
Following the ENTH domain there is not as much conservation in structure across species. However, in higher eukaryotes their are several conserved motifs such as the clathrin - binding motifs which bind clathrin heavy chain, these motifs flank a cluster of up to eight DP repeats which bind to AP2 [1].
Function
[edit]In mammals, the two main classes of Epsin's are expressed through out tissues but has the highest expression in the brain, whereas the third Epsin has higher expression in the epidermis and the stomach [2]. Due to their involvement in cell signaling activation epsins have been implemented to play a role in cell proliferation, differentiation and migration[2]. In addition, epsin has been implemented in the Notch signaling pathway which is critical for normal embryonic development.
In addition to it's primary role as an endocytic adapter, their is evidence the epsins play a role in regulating GTPase activity which provides an alternative mechanism for epsin's role in cell polarity and migration [2].
Role In Notch Signaling
[edit]Notch signaling is dependent on the proteolytic cleabage of the Notch receptor intracellular domain [2]. Epsin's role in Notch signaling is due to Notch's reliance on ligand endocytosis to promote the release of the Notch intracellular domain. This occurs through ubiquitination of the D114 notch ligand which provides a docking location of the epsin UIM domain [2]. Current research suggest that this directing of cargo material aids in the recycling in Notch signaling as well [3].
A study on knock out epsins 1 and 2 in mice showed embryonic death at day 10. Further investigation showed vascular defects in the ebryo proper, placenta and yolk - sac which are characteristic of a lose in notch signaling [2].
Role In Cancer Progression
[edit]Due to epsin's role in the angiogenesis of tumors, epsin has the potential to be a target for anti - cancer therapies. Several cancers including prostate, breast, lung and skin display an upregulation in epsin [2]. Research indicates that the overexpression could affect the regulation of tumor angiogenesis through defects the notch pathway [2].
References
[edit]- ^ a b c d e f g Sen, A; Madhivanan, K; Mukherjee, D; Aguilar, RC (April 2012). "The epsin protein family: coordinators of endocytosis and signaling". Biomolecular concepts. 3 (2): 117–126. PMID 22942912.
- ^ a b c d e f g h i j k Tessneer, KL; Cai, X; Pasula, S; Dong, Y; Liu, X; Chang, B; McManus, J; Hahn, S; Yu, L; Chen, H (1 July 2013). "Epsin Family of Endocytic Adaptor Proteins as Oncogenic Regulators of Cancer Progression". Journal of cancer research updates. 2 (3): 144–150. PMID 24501612.
- ^ a b Musse, AA; Meloty-Kapella, L; Weinmaster, G (June 2012). "Notch ligand endocytosis: mechanistic basis of signaling activity". Seminars in cell & developmental biology. 23 (4): 429–36. PMID 22306180.