title: The three-way switch operation of Rac1/RhoA GTPase-based circuit controlling amoeboid-hybrid-mesenchymal transition.
abstract: Metastatic carcinoma cells exhibit at least two different phenotypes of motility and invasion - amoeboid and mesenchymal. This plasticity poses a major clinical challenge for treating metastasis, while its underlying mechanisms remain enigmatic. Transitions between these phenotypes are mediated by the Rac1/RhoA circuit that responds to external signals such as HGF/SF via c-MET pathway. Using detailed modeling of GTPase-based regulation to study the Rac1/RhoA circuit's dynamics, we found that it can operate as a three-way switch. We propose to associate the circuit's three possible states to the amoeboid, mesenchymal and amoeboid/mesenchymal hybrid phenotype. In particular, we investigated the range of existence of, and the transition between, the three states (phenotypes) in response to Grb2 and Gab1 - two downstream adaptors of c-MET. The results help to explain the regulation of metastatic cells by c-MET pathway and hence can contribute to the assessment of possible clinical interventions.
authors.affiliation: 1] Center for Theoretical Biological Physics, Rice University, Houston, TX 77005-1827, USA [2] Department of Chemistry, Rice University, Houston, TX 77005-1827, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Huang
authors.affiliation: Center for Theoretical Biological Physics, Rice University, Houston, TX 77005-1827, USA.
authors.forename: Mingyang
authors.initials: M
authors.lastname: Lu
authors.affiliation: 1] Center for Theoretical Biological Physics, Rice University, Houston, TX 77005-1827, USA [2] Department of Bioengineering, Rice University, Houston, TX 77005-1827, USA.
authors.forename: Mohit Kumar
authors.initials: MK
authors.lastname: Jolly
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine.
authors.forename: Ilan
authors.initials: I
authors.lastname: Tsarfaty
authors.affiliation: 1] Center for Theoretical Biological Physics, Rice University, Houston, TX 77005-1827, USA [2] Department of Chemistry, Rice University, Houston, TX 77005-1827, USA [3] Department of Physics and Astronomy, Rice University, Houston, TX 77005-1827, USA [4] Department of Biosciences, Rice University, Houston, TX 77005-1827, USA.
authors.forename: José
authors.initials: J
authors.lastname: Onuchic
authors.affiliation: 1] Center for Theoretical Biological Physics, Rice University, Houston, TX 77005-1827, USA [2] Department of Biosciences, Rice University, Houston, TX 77005-1827, USA [3] School of Physics and Astronomy and The Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv 69978, Israel.
authors.forename: Eshel
authors.initials: E
authors.lastname: Ben-Jacob
mesh_terms: D000656:Amoeba / Q000166:cytology* / Q000378:metabolism; D002465:Cell Movement; D048430:Cell Shape; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology*; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein