Chemorepellants and Their Signal Transduction Pathways: Gβ and Akt Proteins Necessary for Dictyostelium AprA Chemorepulsion
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Cellular movement in response to a chemical gradient, known as chemotaxis, is a critical behavior in many developmental and pathological processes such as embryo development and cancer metastasis. This cell movement can be directed toward a chemical source (chemoattraction), or away from a chemical source (chemorepulsion). In certain normal and tumor mammalian cells, there is secretion of chemorepellant signals that causes specific cell types to move away from them. For example, Semaphorin 3A acts as a chemorepellant involved in axon guidance during neuronal development and is implicated in glial cancer cell metastasis (glioblastoma multiforme), but its mechanism of action is not yet well understood. Studies using the eukaryotic unicellular amoeba Dictyostelium discoideum as a model showed that proliferating Dictyostelium cells secrete a protein called AprA, and that AprA is an extracellular signal that functions both as a chemorepellant and an inhibitor of cell proliferation. By analyzing the movement of mutant strains in a gradient of recombinant AprA, the role of specific proteins in the AprA chemorepulsion mechanism was assessed. The proteins CrlA, Gα9 and Gβ have been implicated in AprA cell signaling and growth pathways, but not directly in AprA chemorepulsion signaling. It was found that Gβ, but not Gα9 or CrlA, is necessary for chemorepulsion by AprA. The proteins IplA, Akt1/2, PiaA, Gca/sgcA and PI3K 1/2/3/4/5, are components of other chemotaxis signaling pathways, but are not known to be involved in AprA signaling pathways. This study’s results indicate that of these, only Akt1/2 is necessary for chemorepulsion by AprA. These results indicate that Gβ and Akt1/2 proteins are involved in the chemorepellant signaling pathway for AprA in Dictyostelium discoideum. The presence of functional homologs of Gβ and Akt1/2 proteins in other cells, for example mammalian neutrophils, suggests that they may be involved in a similar chemorepulsion pathway. Through identifying the components of the transduction pathway of chemorepellants such as AprA, the development of novel therapeutics that can modulate this pathway could help lead to improved treatments in cancer and autoimmune disease.
Constantine, Alexander (2013). Chemorepellants and Their Signal Transduction Pathways: Gβ and Akt Proteins Necessary for Dictyostelium AprA Chemorepulsion. Honors and Undergraduate Research. Available electronically from