Diaphanous family of formin protein is important for nucleation and linear elongation and bundling of actin filaments, and operate downstream of p21 small GTPases of the Rho family. The roles of formins and related proteins during motility and invasion process of breast cancers are not clearly known, especially in relation to the downstream specificity of the RhoGTPase isoforms RhoA versus RhoC. Here, we will develop new fluorescent biosensors for Diaphanous family of formins pertinent to this important motility regulatory pathway, useful for molecular and cellular analysis of cancer cells during invasion. The current limitations to better understanding the molecular regulatory pathways controlled by formins including the Diaphanous related formins (DRF) that control and coordinate the motile mechanisms including actin cytoskeleton reorganization, protrusions, and invasive matrix degradation, are due to lack of sophisticated imaging technologies capable of specifically targeting these important signaling nodes in living cells. We will use these new biosensors in combination with our proven biosensors for the Rho GTPases to directly probe the mechanisms these mammalian Diaphanous formin mDia1 and mDia2 isoforms regulate during cancer invasion in invadopodia protrusions of metastatic mammary adenocarcinomas.
In invasive breast adenocarcinomas, the process of invasion through the extracellular matrix during metastasis is tightly regulated and coordinated through mechanisms involving the Rho-family GTPases, resulting in protrusions of invasive processes called invadopodia, which are capable of extracellular matrix degradation. We have previously shown the roles of RhoA, RhoC and Rac1 in regulating differential functions of these invadopodia protrusions. Here, we will use the breast cancer invadopodia compartment as the model system and address the isoform-specific signaling mechanisms by using our new biosensors for the Rho-downstream target mammalian Diaphanous formin 1 and 2 (mDia1, mDia2), to delineate the differential signaling pathways these protein isoforms regulate at invadopodia.
| Wisdom, Katrina M; Adebowale, Kolade; Chang, Julie et al. (2018) Matrix mechanical plasticity regulates cancer cell migration through confining microenvironments. Nat Commun 9:4144 |
| Dufurrena, Quinn; Bäck, Nils; Mains, Richard E et al. (2018) Kalirin/Trio Rho GDP/GTP exchange factors regulate proinsulin and insulin secretion. J Mol Endocrinol : |
| Condon, Nicholas D; Heddleston, John M; Chew, Teng-Leong et al. (2018) Macropinosome formation by tent pole ruffling in macrophages. J Cell Biol 217:3873-3885 |
| Donnelly, Sara K; Miskolci, Veronika; Garrastegui, Alice M et al. (2018) Characterization of Genetically Encoded FRET Biosensors for Rho-Family GTPases. Methods Mol Biol 1821:87-106 |
| Shcherbakova, Daria M; Cox Cammer, Natasha; Huisman, Tsipora M et al. (2018) Direct multiplex imaging and optogenetics of Rho GTPases enabled by near-infrared FRET. Nat Chem Biol 14:591-600 |
| Liu, Jessica Aijia; Rao, Yanxia; Cheung, May Pui Lai et al. (2017) Asymmetric localization of DLC1 defines avian trunk neural crest polarity for directional delamination and migration. Nat Commun 8:1185 |
| Hanna, Samer J; McCoy-Simandle, Kessler; Miskolci, Veronika et al. (2017) The Role of Rho-GTPases and actin polymerization during Macrophage Tunneling Nanotube Biogenesis. Sci Rep 7:8547 |
| Donnelly, Sara K; Cabrera, Ramon; Mao, Serena P H et al. (2017) Rac3 regulates breast cancer invasion and metastasis by controlling adhesion and matrix degradation. J Cell Biol 216:4331-4349 |
| Cao, Longyue L; Riascos-Bernal, Dario F; Chinnasamy, Prameladevi et al. (2016) Control of mitochondrial function and cell growth by the atypical cadherin Fat1. Nature 539:575-578 |
| Franco, Antonietta; Kitsis, Richard N; Fleischer, Julie A et al. (2016) Correcting mitochondrial fusion by manipulating mitofusin conformations. Nature 540:74-79 |
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