Rebecca Cook
Faculty Member
Last active: 4/15/2019

mTOR Directs Breast Morphogenesis through the PKC-alpha-Rac1 Signaling Axis.

Morrison MM, Young CD, Wang S, Sobolik T, Sanchez VM, Hicks DJ, Cook RS, Brantley-Sieders DM
PLoS Genet. 2015 11 (7): e1005291

PMID: 26132202 · PMCID: PMC4488502 · DOI:10.1371/journal.pgen.1005291

Akt phosphorylation is a major driver of cell survival, motility, and proliferation in development and disease, causing increased interest in upstream regulators of Akt like mTOR complex 2 (mTORC2). We used genetic disruption of Rictor to impair mTORC2 activity in mouse mammary epithelia, which decreased Akt phosphorylation, ductal length, secondary branching, cell motility, and cell survival. These effects were recapitulated with a pharmacological dual inhibitor of mTORC1/mTORC2, but not upon genetic disruption of mTORC1 function via Raptor deletion. Surprisingly, Akt re-activation was not sufficient to rescue cell survival or invasion, and modestly increased branching of mTORC2-impaired mammary epithelial cells (MECs) in culture and in vivo. However, another mTORC2 substrate, protein kinase C (PKC)-alpha, fully rescued mTORC2-impaired MEC branching, invasion, and survival, as well as branching morphogenesis in vivo. PKC-alpha-mediated signaling through the small GTPase Rac1 was necessary for mTORC2-dependent mammary epithelial development during puberty, revealing a novel role for Rictor/mTORC2 in MEC survival and motility during branching morphogenesis through a PKC-alpha/Rac1-dependent mechanism.

MeSH Terms (24)

Animals Carrier Proteins Cell Line Cell Movement Cell Survival Female Mammary Glands, Animal Mammary Neoplasms, Animal Mechanistic Target of Rapamycin Complex 1 Mechanistic Target of Rapamycin Complex 2 Mice Mice, Inbred C57BL Mice, Transgenic Morphogenesis Multiprotein Complexes Neoplasm Invasiveness Neuropeptides Organ Culture Techniques Phosphorylation Protein Kinase C-alpha Proto-Oncogene Proteins c-akt rac1 GTP-Binding Protein Rapamycin-Insensitive Companion of mTOR Protein TOR Serine-Threonine Kinases

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