RALA
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1UAD, 1ZC3, 1ZC4, 2A78, 2A9K, 2BOV
Identifiers
Aliases	RALA, RAL, RALA Ras like proto-oncogene A, RAS like proto-oncogene A, HINCONS
External IDs	OMIM: 179550 MGI: 1927243 HomoloGene: 3942 GeneCards: RALA
Gene location (Human) Chr. Chromosome 7 (human)[1] Band 7p14.1 Start 39,623,565 bp[1] End 39,708,120 bp[1]
Gene location (Mouse) Chr. Chromosome 13 (mouse)[2] Band 13 A2|13 6.05 cM Start 18,055,156 bp[2] End 18,118,824 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in secondary oocyte amniotic fluid oral cavity Brodmann area 23 visceral pleura middle temporal gyrus parotid gland endothelial cell jejunal mucosa vulva Top expressed in otic placode saccule medial ganglionic eminence atrioventricular valve maxillary prominence facial motor nucleus endocardial cushion neural tube medullary collecting duct renal corpuscle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function Edg-2 lysophosphatidic acid receptor binding nucleotide binding GDP binding myosin binding ATPase binding GTP binding protein binding GTPase activity ubiquitin protein ligase binding Cellular component membrane focal adhesion myelin sheath plasma membrane endocytic vesicle cleavage furrow extracellular exosome cytoplasmic vesicle membrane cell surface Flemming body intracellular anatomical structure Biological process actin cytoskeleton reorganization cell division regulation of exocytosis chemotaxis neural tube closure membrane raft localization cell cycle membrane organization viral process positive regulation of filopodium assembly signal transduction exocytosis Ras protein signal transduction interleukin-12-mediated signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 5898 56044 Ensembl ENSG00000006451 ENSMUSG00000008859 UniProt P11233 P63321 RefSeq (mRNA) NM_005402 NM_019491 RefSeq (protein) NP_005393 NP_062364 Location (UCSC) Chr 7: 39.62 – 39.71 Mb Chr 13: 18.06 – 18.12 Mb PubMed search [3] [4]
Wikidata
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Ras-related protein Ral-A (RalA) is a protein that in humans is encoded by the RALA gene on chromosome 7.^[5][6] This protein is one of two paralogs of the Ral protein, the other being RalB, and part of the Ras GTPase family.^[7] RalA functions as a molecular switch to activate a number of biological processes, majorly cell division and transport, via signaling pathways.^[7][8][9] Its biological role thus implicates it in many cancers.^[9]

Structure

The Ral isoforms share an 80% overall match in amino acid sequence and 100% match in their effector-binding region. The two isoforms mainly differ in the C-terminal hypervariable region, which contains multiple sites for post-translational modification, leading to diverging subcellular localization and biological function. For example, phosphorylation of Serine 194 on RalA by the kinase Aurora A results in the relocation of RalA to the inner mitochondrial membrane, where RalA helps carry out mitochondrial fission; whereas phosphorylation of Serine 198 on RalB by the kinase PKC results in the relocation of RalB to other internal membranes and activation of its tumorigenic function.^[9]

Function

RalA is one of two proteins in the Ral family, which is itself a subfamily within the Ras family of small GTPases.^[7] As a Ras GTPase, RalA functions as a molecular switch that becomes active when bound to GTP and inactive when bound to GDP. RalA can be activated by RalGEFs and, in turn, activate effectors in signal transduction pathways leading to biological outcomes.^[7][8] For instance, RalA interacts with two components of the exocyst, Exo84 and Sec5, to promote autophagosome assembly, secretory vesicle trafficking, and tethering. Other downstream functions include exocytosis, receptor-mediated endocytosis, tight junction biogenesis, filopodia formation, mitochondrial fission, and cytokinesis.^[7][9][10] Ral-mediated exocytosis is also involved such biological processes as platelet activation, immune cell functions, neuronal plasticity, and regulation of insulin action.^[11]

While the above functions appear to be shared between the two Ral isoforms, their differential subcellular localizations result in their differing involvement in certain biological processes. In particular, RalA is more involved in anchorage-independent cell growth, vesicle trafficking, and cytoskeletal organization.^[8][12] Moreover, RalA specifically interacts with Exo84 and Sec5 to regulate transport of membrane proteins in polarized epithelial cells and GLUT4 to the plasma membrane, as well as mitochondrial fission for cell division.^[7]

Clinical significance

Ral proteins have been associated with the progression of several cancers, including bladder cancer and prostate cancer.^[9] Though the exact mechanisms remain unclear, studies reveal that RalA promotes anchorage-independent growth in cancer cells.^[8] As a result, inhibition of RalA inhibits cancer initiation.^[9]

Due to its exocytotic role in platelets, immune cells, neurons, and insulin regulation, downregulation of Ral may lead to pathological conditions such as thrombosis and metabolic syndrome. In chronic thromboembolic pulmonary hypertension patients, Ral GTPases have been observed to be highly active in their platelets.^[11]

Interactions

RalA has been shown to interact with:

• EXOC8,^[7]
• Filamin,^[13]
• PLD1,^[14][15]
• Sec5,^[7][9] and
• RALBP1.^{[16][17][18][19]}