Limits...
LKB1 kinase-dependent and -independent defects disrupt polarity and adhesion signaling to drive collagen remodeling during invasion.

Konen J, Wilkinson S, Lee B, Fu H, Zhou W, Jiang Y, Marcus AI - Mol. Biol. Cell (2016)

Bottom Line: The majority of LKB1 mutations are truncations that disrupt its kinase activity and remove its C-terminal domain (CTD).Instead, cell polarity is overseen by the kinase-independent function of its CTD and more specifically its farnesylation.This occurs through a mesenchymal-amoeboid morphological switch that signals through the Rho-GTPase RhoA.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA 30322 Graduate Program in Cancer Biology, Emory University, Atlanta, GA 30322.

No MeSH data available.


Related in: MedlinePlus

Model. LKB1 provides kinase-dependent and -independent mechanisms of regulating cell polarity during invasion. Through the LKB1 CTD and its farnesylation, LKB1 activates the Rho-GTPase RhoA to promote mesenchymal polarization and strong directional persistence during invasion. Independent of its CTD, LKB1 kinase activity phosphorylates MARK1 to repress the active form of focal adhesion kinase (pFAK), leading to regulation of focal adhesion dynamics and collagen remodeling during 3D invasion.
© Copyright Policy - creative-commons
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4814216&req=5

Figure 9: Model. LKB1 provides kinase-dependent and -independent mechanisms of regulating cell polarity during invasion. Through the LKB1 CTD and its farnesylation, LKB1 activates the Rho-GTPase RhoA to promote mesenchymal polarization and strong directional persistence during invasion. Independent of its CTD, LKB1 kinase activity phosphorylates MARK1 to repress the active form of focal adhesion kinase (pFAK), leading to regulation of focal adhesion dynamics and collagen remodeling during 3D invasion.

Mentions: The functional diversity of LKB1 has been attributed to it phosphorylating 14 members of the AMPK family of proteins, which, when activated, regulate a diverse set of biological processes (Lizcano et al., 2004; Jaleel et al., 2005; Hardie and Alessi, 2013). However, multiple reports show a kinase-independent function of LKB1 that is linked to cell polarity (Lo et al., 2012; Nakano and Takashima, 2012). Because a majority of the truncating mutations (Cancer Genome Atlas Research Network, 2014; ∼72% of LKB1 mutations in lung adenocarcinoma patients; Figure 2A) would predictably disrupt its kinase activity and remove its C-terminal domain, we sought to uncouple defects in CTD function from defects in kinase function in the context of cancer cell invasion. These results support an overall model in which the LKB1 CTD regulates cell polarization through a mesenchymal–amoeboid cell switch, whereas the kinase domain regulates FAK-based cell adhesion during invasion. These results suggest that when both kinase activity and CTD function are compromised, both aberrant cell polarity and adhesion programs ensue. Our data indicate that this is indeed the case; complete LKB1 depletion creates a uniquely invasive, amoeboid-shaped cell that, in contrast to typical amoeboid cells (Mandeville et al., 1997; Friedl et al., 1998; Friedl and Wolf, 2003), maintains a hyperactive FAK-based cell adhesion program and remodels collagen. We speculate that truncating mutations in LKB1 mutant patients might create a similar scenario (Figure 9), in which both CTD and kinase function is disrupted, leading to increased invasiveness by creating an agile cell that can be amoeboid, adherent, and able to navigate the tumor microenvironment.


LKB1 kinase-dependent and -independent defects disrupt polarity and adhesion signaling to drive collagen remodeling during invasion.

Konen J, Wilkinson S, Lee B, Fu H, Zhou W, Jiang Y, Marcus AI - Mol. Biol. Cell (2016)

Model. LKB1 provides kinase-dependent and -independent mechanisms of regulating cell polarity during invasion. Through the LKB1 CTD and its farnesylation, LKB1 activates the Rho-GTPase RhoA to promote mesenchymal polarization and strong directional persistence during invasion. Independent of its CTD, LKB1 kinase activity phosphorylates MARK1 to repress the active form of focal adhesion kinase (pFAK), leading to regulation of focal adhesion dynamics and collagen remodeling during 3D invasion.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4814216&req=5

Figure 9: Model. LKB1 provides kinase-dependent and -independent mechanisms of regulating cell polarity during invasion. Through the LKB1 CTD and its farnesylation, LKB1 activates the Rho-GTPase RhoA to promote mesenchymal polarization and strong directional persistence during invasion. Independent of its CTD, LKB1 kinase activity phosphorylates MARK1 to repress the active form of focal adhesion kinase (pFAK), leading to regulation of focal adhesion dynamics and collagen remodeling during 3D invasion.
Mentions: The functional diversity of LKB1 has been attributed to it phosphorylating 14 members of the AMPK family of proteins, which, when activated, regulate a diverse set of biological processes (Lizcano et al., 2004; Jaleel et al., 2005; Hardie and Alessi, 2013). However, multiple reports show a kinase-independent function of LKB1 that is linked to cell polarity (Lo et al., 2012; Nakano and Takashima, 2012). Because a majority of the truncating mutations (Cancer Genome Atlas Research Network, 2014; ∼72% of LKB1 mutations in lung adenocarcinoma patients; Figure 2A) would predictably disrupt its kinase activity and remove its C-terminal domain, we sought to uncouple defects in CTD function from defects in kinase function in the context of cancer cell invasion. These results support an overall model in which the LKB1 CTD regulates cell polarization through a mesenchymal–amoeboid cell switch, whereas the kinase domain regulates FAK-based cell adhesion during invasion. These results suggest that when both kinase activity and CTD function are compromised, both aberrant cell polarity and adhesion programs ensue. Our data indicate that this is indeed the case; complete LKB1 depletion creates a uniquely invasive, amoeboid-shaped cell that, in contrast to typical amoeboid cells (Mandeville et al., 1997; Friedl et al., 1998; Friedl and Wolf, 2003), maintains a hyperactive FAK-based cell adhesion program and remodels collagen. We speculate that truncating mutations in LKB1 mutant patients might create a similar scenario (Figure 9), in which both CTD and kinase function is disrupted, leading to increased invasiveness by creating an agile cell that can be amoeboid, adherent, and able to navigate the tumor microenvironment.

Bottom Line: The majority of LKB1 mutations are truncations that disrupt its kinase activity and remove its C-terminal domain (CTD).Instead, cell polarity is overseen by the kinase-independent function of its CTD and more specifically its farnesylation.This occurs through a mesenchymal-amoeboid morphological switch that signals through the Rho-GTPase RhoA.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA 30322 Graduate Program in Cancer Biology, Emory University, Atlanta, GA 30322.

No MeSH data available.


Related in: MedlinePlus