Proper regulation of cell polarity and motility is critical for maintaining normal physiology, and loss of proper cell polarity can result in tumor development. Better understanding how cell polarity is regulated is critical for understanding how aberrant polarity leads to tumor development. Cell polarity is regulated through a dynamic series of protein interactions, including the Rho family of GTPases, master regulators of cell polarity and motility. We and others have identified a novel regulator of the Rho-GTPase family, the serine/threonine kinase Liver Kinase B1 (LKB1, also known as STK11), which is highly mutated in lung cancer cells. Specifically, we have published that LKB1 associates with the Rho-GTPase cdc42 in lamellipodia at the cellular leading edge to regulate cell polarity, though the precise mechanism of this association remains unclear. LKB1 contains a C- terminal farnesylation motif to allow for plasma membrane insertion and our preliminary data indicate farnesylation is critical for maintenance of proper cell polarity. Additionally, we show that LKB1 associates with leading edge actin, also through its C-terminal domain, to regulate cell motility, and this association occurs in a farnesylation-dependent manner. Given that LKB1 farnesylation is required for maintaining proper cell polarity and associating with actin, we will test the centrl hypothesis that farnesylated LKB1 is required for formation of the LKB1:Rho-GTPase complex, regulating cell polarity to inhibit cellular invasion and metastasis through regulation of localize actin polymerization. To test this, we will determine: 1) whether LKB1 farnesylation promotes its association with Rho-GTPases to regulate cell polarity and invasion, and 2), whether LKB1 complexes with cdc42 to promote actin polymerization.
In Aim 1, we will determine whether LKB1 farnesylation is required for it to associate with Rho-GTPases, and whether this association is required for proper cell polarity in vitro, and whether it regulates cell invasion ad metastasis in vivo.
In Aim 2, we will use Total Internal Reflection Fluorescence (TIRF) microscopy to determine whether farnesylated LKB1 complexes with cdc42 to promote leading edge actin polymerization, and whether LKB1 acts synergistically with cdc42 to promote actin polymerization in vitro. This work will advance our understanding of basic cell polarity and how LKB1 regulates polarity and invasion. Moreover, since LKB1 is frequently mutated in lung cancer, this research will provide insight into the basic cellular mechanisms guiding the early stages of lung cancer invasion.
Normal cell development and function is maintained through a variety of regulatory proteins, including proteins that regulate cell shape and movement. When these proteins no longer properly regulate shape and movement, cells can lose their normal stationary function and instead develop into cancer. This research will study how proteins regulate normal cell shape and movement, and why mutations in these proteins can result in tumor development, allowing us to develop new medications to target the early stages of tumor development.
| Wilkinson, S; Hou, Y; Zoine, J T et al. (2017) Coordinated cell motility is regulated by a combination of LKB1 farnesylation and kinase activity. Sci Rep 7:40929 |
| Lee, Byoungkoo; Konen, Jessica; Wilkinson, Scott et al. (2017) Local alignment vectors reveal cancer cell-induced ECM fiber remodeling dynamics. Sci Rep 7:39498 |
| Konen, Jessica; Wilkinson, Scott; Lee, Byoungkoo et al. (2016) LKB1 kinase-dependent and -independent defects disrupt polarity and adhesion signaling to drive collagen remodeling during invasion. Mol Biol Cell 27:1069-84 |
| Liu, Fakeng; Jin, Rui; Liu, Xiuju et al. (2016) LKB1 promotes cell survival by modulating TIF-IA-mediated pre-ribosomal RNA synthesis under uridine downregulated conditions. Oncotarget 7:2519-31 |
