Genetic deletion of RALA and RALB small GTPases reveals redundant functions in development and tumorigenesis.
RAL small GTPases, encoded by the Rala and Ralb genes, are members of the RAS superfamily of small GTPases and can act as downstream effectors of RAS [1]. Although highly similar, distinct functions have been identified for RALA and RALB: RALA has been implicated in epithelial cell polarity [2], insulin secretion [3], GLUT4 translocation [4, 5], neurite branching, and neuronal polarity [6, 7], and RALB in tumor cell survival [8], migration/invasion [9-12], TBK1 activation [13], and autophagy [14]. To investigate RAL GTPases in vivo, we generated null and conditional knockout mice. Ralb null mice are viable with no overt phenotype; the Rala null leads to exencephaly and embryonic lethality. The exencephaly phenotype is exacerbated in Rala(-/-);Ralb(+/-) embryos; embryos null for Rala and Ralb do not live past gastrulation. Using a Kras-driven non-small cell lung carcinoma mouse model, we found that either RALA or RALB is sufficient for tumor growth. However, deletion of both Ral genes blocks tumor formation. Either RALA or RALB is sufficient for cell proliferation, but cells lacking both fail to proliferate. These studies demonstrate functions of RAL proteins in development, tumorigenesis, and cell proliferation and show that RALA and RALB act in a redundant fashion.
Oncogene Team, Division of Cancer Biology, Institute of Cancer Research, London SW3 6JB, UK.
Pascal
P
Peschard
Afshan
A
McCarthy
Valérie
V
Leblanc-Dominguez
Maggie
M
Yeo
Sabrina
S
Guichard
Gordon
G
Stamp
Christopher J
CJ
Marshall
D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology; D016764:Cell Polarity; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D047108:Embryonic Development; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054259:Neural Tube / Q000196:embryology / Q000378:metabolism; D009436:Neural Tube Defects / Q000235:genetics; D015689:Oncogene Protein p21(ras) / Q000378:metabolism; D015398:Signal Transduction; D020725:ral GTP-Binding Proteins / Q000235:genetics / Q000502:physiology*
C118120:Rala protein, mouse; D015689:Oncogene Protein p21(ras); C535173:RalB protein, mouse; D020725:ral GTP-Binding Proteins