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Phenotypic plasticity is the ability of cells to switch to different states (phenotypes) based on environmental cues, without any change in the underlying genotype. This non-genetic heterogeneity has recently gathered much attention in cancer biology. Cancer cells exhibit plasticity in response to cell adhesion signaling. The ability to survive lack of adhesion, called anoikis resistance, is a hallmark feature of metastatic cancers. Cancer cells undergo a metabolic switch in response to lack of adhesion that allows them to survive in circulation. A double negative feedback loop between AMP-activated protein kinase (AMPK) and AKT governs the metabolic phenotype of cancer cells. Calcium and redox signaling mediate the rapid activation of AMPK in anchorage-deprived conditions (1). This AMPKhigh/AKTlow state in detached cells converts them into a catabolic phenotype. Metabolic plasticity allows cancer cells to survive the metastasis cascade.
The microvasculature of our body is highly plastic and capable of continuous structural change in response to various functional demands and diseases. Endothelial cells are capable of rapidly switching from quiescent to angiogenic state and back in response to the external milieu. Rho GTPases are a group of proteins involved in the cytoskeletal reorganization allowing endothelial cells to change shape and polarity. Rho GTPases drive endothelial motility and capillary formation (2). RhoJ is an endothelium-specific Rho GTPase (3) with a vesicular distribution. Through targeted vesicle purification and proteomics, we identify active integrin 51 as a RhoJ dependent cargo. RhoJ inhibits active integrin 51 trafficking thereby repressing fibronectin remodeling in endothelial cells. RhoJ has arisen by a gene duplication in the ancestral Cdc42 gene and the two proteins share most of the effectors. Our study shows that the ability to remodel fibronectin is fine-tuned by the opposing actions of RhoJ and Cdc42. Intriguingly, this is achieved through competition for the limiting effector protein, PAK3. Lack of RhoJ in mice causes deregulated fibronectin deposition at the angiogenic front. We identify a temporal switch in the activation of RhoJ and Cdc42 that governs the plasticity in vesicular trafficking of active integrin 51 to regulate matrix remodeling in endothelial cells.
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