# RALB

## Overview
RALB is a gene that encodes the RAS-like proto-oncogene B, a member of the RAS superfamily of small GTPases. This protein plays a pivotal role in various cellular processes, including the regulation of tight junctions, cell polarity, and autophagy. As a small GTPase, RALB functions as a molecular switch, cycling between active GTP-bound and inactive GDP-bound states, thereby influencing signal transduction pathways that control cell growth, survival, and differentiation (Fenwick2010The; Chien2006RalB). The protein's interactions with components of the exocyst complex, such as Sec5 and Exo84, are critical for its involvement in immune signaling and autophagosome assembly (Bodemann2011RalB; Chien2006RalB). Dysregulation of RALB expression has been linked to various cancers, underscoring its potential as a therapeutic target (Zhou2024Identification; Khawaja2020RALB).

## Structure
The RALB protein, a member of the RAS superfamily of small GTPases, exhibits a complex molecular structure that includes several key features. Its primary structure consists of a sequence of amino acids that form a GTP-binding domain, essential for its function in cellular signaling pathways (Fenwick2010The). The secondary structure of RALB includes alpha helices and beta sheets, with the RLIP76 GTPase-binding domain (GBD) forming an antiparallel coiled-coil structure comprising two alpha helices, a common motif for binding small G proteins (Fenwick2010The).

In terms of tertiary structure, the RALB protein undergoes conformational changes upon binding to effectors like RLIP76, with specific interactions involving the switch regions of RALB, which are crucial for effector binding (Fenwick2010The). The quaternary structure involves the interaction of RALB with other proteins, such as RLIP76, forming a complex that is stabilized by hydrophobic interactions and specific residue contacts (Fenwick2010The).

Post-translational modifications of RALB include lysine fatty acylation, particularly at Lys200, which enhances its plasma membrane localization and interaction with effector proteins like Sec5 and Exo84 (Spiegelman2019SIRT2). This modification is crucial for its role in cellular processes such as migration and exocytosis (Spiegelman2019SIRT2).

## Function
RALB, a member of the RAS superfamily of small GTPases, plays a significant role in various cellular processes, particularly in the regulation of tight junctions (TJs) and cell polarity. In epithelial cells, RALB is involved in the endocytosis of junction proteins, which is crucial for maintaining cell-cell contacts and TJ integrity. Knockdown studies have shown that RALB affects the incorporation and stability of TJ proteins, such as ZO-1, claudin1, claudin4, and occludin, by promoting their endocytosis, thereby influencing the permeability and electrical barrier of epithelial monolayers (Hazelett page 7 of 21; Hazelett page 8 of 21).

RALB also plays a role in ciliogenesis and cystogenesis, where it is implicated in the endocytosis and recycling of primary cilia components, potentially through interactions with the Exocyst complex. This activity affects the length of primary cilia and the formation of multiple lumens during cystogenesis (Hazelett page 20 of 21; Hazelett page 17 of 21).

In the context of neurite branching, RALB is involved in cytoskeletal reorganization and endocytic recycling, coordinating these processes in response to extracellular matrix stimuli. It interacts with GAP-43 and the Exocyst complex, contributing to the stabilization of growth cone interactions and promoting actin polymerization, which are essential for neurite branching (Lalli2005Ral).

## Clinical Significance
Alterations in the expression of the RALB gene have been implicated in various cancers, highlighting its clinical significance. In KRAS mutant colorectal cancer (CRC), RALB plays a crucial role in regulating DR5 expression and TRAIL sensitivity. High RALB expression is associated with poor prognosis, particularly in the CRIS-B CRC subgroup, which is characterized by invasive features and poor outcomes. Targeting RALB in combination with DR5 agonists has been suggested as a potential therapeutic strategy for these patients (Khawaja2020RALB).

In head and neck squamous cell carcinoma (HNSCC), RALB expression is significantly upregulated compared to normal tissues. High RALB expression correlates with worse prognosis, including lower overall survival rates and increased lymph node metastasis. This suggests that RALB could serve as a prognostic marker and therapeutic target in HNSCC (Zhou2024Identification).

In acute myeloid leukemia (AML), RALB is essential for the survival of malignant cells, and its signaling is hyperactivated in patient samples. The drug dinaciclib has shown RALB-dependent anti-leukemic effects, indicating that targeting RALB could have therapeutic implications in AML and other Ras-driven cancers (Pomeroy2017Targeting).

## Interactions
RALB interacts with several proteins, playing a crucial role in various cellular processes. It forms a complex with RLIP76 (also known as RalBP1), where the interaction involves specific residues in the switch regions of RALB, such as Asp-74, Tyr-75, and Ala-76, which interact with residues like His-413 and Leu-416 of RLIP76. This interaction is characterized by hydrophobic contacts and is essential for the binding specificity of RALB to RLIP76 (Fenwick2010The).

RALB also interacts with components of the exocyst complex, including Sec5 and Exo84. The interaction with Sec5 is significant for the activation of TBK1, a kinase involved in immune signaling and cancer cell survival. RALB, when bound to GTP, facilitates the assembly of the Sec5/TBK1 complex, enhancing TBK1 activity (Chien2006RalB). In the context of autophagy, RALB interacts with Exo84 to promote autophagosome assembly, particularly under nutrient starvation conditions. This interaction is crucial for the formation of complexes with Beclin1, a key autophagy protein, and the recruitment of VPS34, a lipid kinase involved in autophagy initiation (Bodemann2011RalB).


## References


[1. (Lalli2005Ral) Giovanna Lalli and Alan Hall. Ral gtpases regulate neurite branching through gap-43 and the exocyst complex. The Journal of Cell Biology, 171(5):857–869, December 2005. URL: http://dx.doi.org/10.1083/jcb.200507061, doi:10.1083/jcb.200507061. This article has 129 citations.](https://doi.org/10.1083/jcb.200507061)

[2. (Bodemann2011RalB) Brian O. Bodemann, Anthony Orvedahl, Tzuling Cheng, Rosalyn R. Ram, Yi-Hung Ou, Etienne Formstecher, Mekhala Maiti, C. Clayton Hazelett, Eric M. Wauson, Maria Balakireva, Jacques H. Camonis, Charles Yeaman, Beth Levine, and Michael A. White. Ralb and the exocyst mediate the cellular starvation response by direct activation of autophagosome assembly. Cell, 144(2):253–267, January 2011. URL: http://dx.doi.org/10.1016/j.cell.2010.12.018, doi:10.1016/j.cell.2010.12.018. This article has 360 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/j.cell.2010.12.018)

[3. (Khawaja2020RALB) Hajrah Khawaja, Andrew Campbell, Jamie Z. Roberts, Arman Javadi, Paul O’Reilly, Darragh McArt, Wendy L. Allen, Joanna Majkut, Markus Rehm, Alberto Bardelli, Federica Di Nicolantonio, Christopher J. Scott, Richard Kennedy, Nicolas Vitale, Timothy Harrison, Owen J. Sansom, Daniel B. Longley, Emma Evergren, and Sandra Van Schaeybroeck. Ralb gtpase: a critical regulator of dr5 expression and trail sensitivity in kras mutant colorectal cancer. Cell Death & Disease, October 2020. URL: http://dx.doi.org/10.1038/s41419-020-03131-3, doi:10.1038/s41419-020-03131-3. This article has 15 citations.](https://doi.org/10.1038/s41419-020-03131-3)

[4. (Chien2006RalB) Yuchen Chien, Sungchan Kim, Ron Bumeister, Yueh-Ming Loo, Sung Won Kwon, Cynthia L. Johnson, Mirey G. Balakireva, Yves Romeo, Levy Kopelovich, Michael Gale, Charles Yeaman, Jacques H. Camonis, Yingming Zhao, and Michael A. White. Ralb gtpase-mediated activation of the iκb family kinase tbk1 couples innate immune signaling to tumor cell survival. Cell, 127(1):157–170, October 2006. URL: http://dx.doi.org/10.1016/j.cell.2006.08.034, doi:10.1016/j.cell.2006.08.034. This article has 309 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/j.cell.2006.08.034)

[5. (Spiegelman2019SIRT2) Nicole A. Spiegelman, Xiaoyu Zhang, Hui Jing, Ji Cao, Ilana B. Kotliar, Pornpun Aramsangtienchai, Miao Wang, Zhen Tong, Kelly M. Rosch, and Hening Lin. Sirt2 and lysine fatty acylation regulate the activity of ralb and cell migration. ACS Chemical Biology, 14(9):2014–2023, August 2019. URL: http://dx.doi.org/10.1021/acschembio.9b00492, doi:10.1021/acschembio.9b00492. This article has 28 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1021/acschembio.9b00492)

[6. (Zhou2024Identification) Zi-Yuan Zhou. Identification of ras-like oncoprotein b (ralb) as a potential prognostic and therapeutic target in head and neck squamous cell carcinoma. American Journal of Translational Research, 16(8):3950–3963, 2024. URL: http://dx.doi.org/10.62347/ndfc4209, doi:10.62347/ndfc4209. This article has 0 citations and is from a peer-reviewed journal.](https://doi.org/10.62347/ndfc4209)

[7. (Fenwick2010The) R. Brynmor Fenwick, Louise J. Campbell, Karthik Rajasekar, Sunil Prasannan, Daniel Nietlispach, Jacques Camonis, Darerca Owen, and Helen R. Mott. The ralb-rlip76 complex reveals a novel mode of ral-effector interaction. Structure, 18(8):985–995, August 2010. URL: http://dx.doi.org/10.1016/j.str.2010.05.013, doi:10.1016/j.str.2010.05.013. This article has 38 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/j.str.2010.05.013)

[8. (Pomeroy2017Targeting) Emily J. Pomeroy and Craig E. Eckfeldt. Targeting ras signaling in aml: ralb is a small gtpase with big potential. Small GTPases, 11(1):39–44, July 2017. URL: http://dx.doi.org/10.1080/21541248.2017.1339765, doi:10.1080/21541248.2017.1339765. This article has 8 citations and is from a peer-reviewed journal.](https://doi.org/10.1080/21541248.2017.1339765)