# RASEF

## Overview
RASEF (RAS and EF-hand domain containing) is a gene that encodes a multifunctional protein involved in intracellular signaling and cytoskeletal organization. The protein, also known as Rab45, is characterized by its RAS domain, which confers small GTPase activity, and an EF-hand domain, which is involved in calcium binding. These structural features suggest that the RASEF protein plays a significant role in vesicle trafficking and cellular movement, primarily functioning within the cytoplasm. It is implicated in the regulation of cell cycle progression, migration, and signaling pathways, including the modulation of the AKT signaling pathway, which is crucial for cell survival and proliferation. RASEF's interactions with other proteins, such as ERK1/2, and its involvement in microtubule transport further highlight its importance in cellular dynamics. Clinically, RASEF has been associated with various cancers, including melanoma and lung cancer, where it may act as a tumor suppressor or be involved in cancer progression, depending on the context (Shintani2007Characterization; Li2019Role; Oshita2013RASEF).

## Structure
RASEF, also known as Rab45, is a protein characterized by its unique molecular structure, which includes several distinct domains. The protein contains an N-terminal EF-hand domain, a mid-region with a coiled-coil motif, and a C-terminal Rab-homology domain. The EF-hand domain is typically involved in calcium ion binding, although its specific role in RASEF is not fully detailed in the available literature (Shintani2007Characterization).

The coiled-coil motif, located between residues 170 and 362, facilitates protein oligomerization and is critical for the self-interaction of RASEF. This self-association is independent of the guanine-nucleotide form of the protein and is essential for its perinuclear localization in cells (Shintani2007Characterization).

The Rab-homology domain at the C-terminal end is responsible for binding guanine nucleotides, specifically GTP and GDP, which is a common feature among Rab-family GTPases. This domain plays a crucial role in the protein's function related to membrane trafficking (Shintani2007Characterization).

RASEF's localization and function are influenced by its guanine nucleotide-bound states, with specific mutants showing altered binding states and localization patterns (Shintani2007Characterization). The protein's expression is noted to be decreased in cutaneous malignant melanoma, although the physiological implications of this are not fully understood (Shintani2007Characterization).

## Function
RASEF (RAS and EF-hand domain containing) is a gene that encodes a protein involved in intracellular signaling and cytoskeletal organization. The protein contains a RAS domain, which is associated with small GTPase activity, and an EF-hand domain, which is involved in calcium binding. These domains suggest that RASEF plays a role in processes such as vesicle trafficking and cellular movement, primarily functioning in the cytoplasm (Li2019Role).

In healthy human cells, RASEF is implicated in the regulation of cell cycle progression, migration, and signaling pathways. It has been shown to modulate the AKT signaling pathway, which is crucial for cell survival and proliferation (Li2019Role). The protein's involvement in these pathways indicates its potential role in maintaining normal cellular functions and preventing abnormal cell growth.

RASEF's activity in the cytoplasm and its interaction with calcium ions through the EF-hand domain suggest that it may also be involved in calcium-dependent signaling pathways, which are essential for various cellular processes, including muscle contraction and neurotransmitter release (Li2019Role). These functions highlight the importance of RASEF in maintaining cellular homeostasis and its potential impact on organismal health.

## Clinical Significance
RASEF has been implicated in several cancers, including melanoma, lung cancer, and uveal melanoma, due to its role in cell signaling and tumor suppression. In melanoma, RASEF is often epigenetically silenced through promoter hypermethylation, which is associated with decreased mRNA expression and contributes to melanoma progression by facilitating increased cell proliferation and reduced senescence (Kaplon2014Near‐genomewide). This silencing is not commonly observed in benign nevi, highlighting its potential role as a tumor suppressor specifically in malignant contexts (Kaplon2014Near‐genomewide).

In lung cancer, RASEF is overexpressed and interacts with ERK1/2, enhancing ERK1/2 phosphorylation, which is crucial for cell proliferation. This interaction is significant in lung cancer pathogenesis, and inhibiting it can suppress lung cancer cell growth, suggesting RASEF as a potential therapeutic target (Oshita2013RASEF). High RASEF expression is linked to poor prognosis in non-small cell lung cancer (NSCLC) patients (Oshita2013RASEF).

In uveal melanoma, RASEF acts as a tumor suppressor, with promoter methylation and reduced expression associated with increased risk of metastasis and decreased survival (Maat2008Epigenetic). These findings underscore the clinical significance of RASEF in cancer development and progression.

## Interactions
RASEF, also known as Rab45, is involved in several protein interactions that are crucial for its function in cellular processes. It interacts with ERK1/2, enhancing ERK1/2 signaling, which can be inhibited to suppress lung cancer cell growth (Tsukuba2021Large). RASEF also forms oligomers, as demonstrated by co-transfection and immunoprecipitation assays, indicating its ability to self-associate (Shintani2007Characterization). This self-interaction is facilitated by the coiled-coil domain (CCD) in its mid-region, which is essential for its oligomerization and intracellular localization (Shintani2007Characterization).

RASEF is associated with the dynein-dynactin complex, suggesting a role in microtubule transport (Tsukuba2021Large). The protein's interaction properties are influenced by its guanine nucleotide-bound states, with the GTP-bound form localizing to the perinuclear compartment (Shintani2007Characterization). These interactions highlight RASEF's involvement in signaling pathways and cellular dynamics, potentially impacting cancer cell behavior and microtubule transport processes.


## References


[1. (Kaplon2014Near‐genomewide) Joanna Kaplon, Cornelia Hömig‐Hölzel, Linda Gao, Katrin Meissl, Els M. E. Verdegaal, Sjoerd H. van der Burg, Remco van Doorn, and Daniel S. Peeper. Near‐genomewide <scp>rna</scp>i screening for regulators of <scp>brafv</scp>600e‐induced senescence identifies <scp>rasef</scp>, a gene epigenetically silenced in melanoma. Pigment Cell &amp; Melanoma Research, 27(4):640–652, May 2014. URL: http://dx.doi.org/10.1111/pcmr.12248, doi:10.1111/pcmr.12248. This article has 15 citations.](https://doi.org/10.1111/pcmr.12248)

[2. (Oshita2013RASEF) Hideto Oshita, Ryohei Nishino, Atsushi Takano, Takashi Fujitomo, Masato Aragaki, Tatsuya Kato, Hirohiko Akiyama, Eiju Tsuchiya, Nobuoki Kohno, Yusuke Nakamura, and Yataro Daigo. Rasef is a novel diagnostic biomarker and a therapeutic target for lung cancer. Molecular Cancer Research, 11(8):937–951, August 2013. URL: http://dx.doi.org/10.1158/1541-7786.mcr-12-0685-t, doi:10.1158/1541-7786.mcr-12-0685-t. This article has 35 citations and is from a peer-reviewed journal.](https://doi.org/10.1158/1541-7786.mcr-12-0685-t)

[3. (Maat2008Epigenetic) Willem Maat, Sigrid H. W. Beiboer, Martine J. Jager, Gre´ P. M. Luyten, Nelleke A. Gruis, and Pieter A. van der Velden. Epigenetic regulation identifiesrasefas a tumor-suppressor gene in uveal melanoma. Investigative Opthalmology &amp; Visual Science, 49(4):1291, April 2008. URL: http://dx.doi.org/10.1167/iovs.07-1135, doi:10.1167/iovs.07-1135. This article has 36 citations.](https://doi.org/10.1167/iovs.07-1135)

[4. (Shintani2007Characterization) Mami Shintani, Minoru Tada, Tetsuo Kobayashi, Hiroaki Kajiho, Kenji Kontani, and Toshiaki Katada. Characterization of rab45/rasef containing ef-hand domain and a coiled-coil motif as a self-associating gtpase. Biochemical and Biophysical Research Communications, 357(3):661–667, June 2007. URL: http://dx.doi.org/10.1016/j.bbrc.2007.03.206, doi:10.1016/j.bbrc.2007.03.206. This article has 28 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.bbrc.2007.03.206)

[5. (Tsukuba2021Large) Takayuki Tsukuba, Yu Yamaguchi, and Tomoko Kadowaki. Large rab gtpases: novel membrane trafficking regulators with a calcium sensor and functional domains. International Journal of Molecular Sciences, 22(14):7691, July 2021. URL: http://dx.doi.org/10.3390/ijms22147691, doi:10.3390/ijms22147691. This article has 11 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/ijms22147691)

[6. (Li2019Role) Qinghai Li, Jixing Wu, Yongjian Xu, Lu Liu, and Jungang Xie. Role of rasef hypermethylation in cigarette smoke-induced pulmonary arterial smooth muscle remodeling. Respiratory Research, March 2019. URL: http://dx.doi.org/10.1186/s12931-019-1014-1, doi:10.1186/s12931-019-1014-1. This article has 11 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1186/s12931-019-1014-1)