Abstract
Liver kinase β1 (LKB1, also known as STK11) is a serine/threonine kinase that has multiple cellular functions including the regulation of cell polarity and motility. Murine proteomic studies show that LKB1 loss causes aberrant adhesion signaling; however, the mechanistic underpinnings of this relationship are unknown. We show that cells stably depleted of LKB1 or its co-activator STRADα have increased phosphorylation of focal adhesion kinase (FAK) at Tyr(397)/Tyr(861) and enhanced adhesion to fibronectin. LKB1 associates in a complex with FAK and LKB1 accumulation at the cellular leading edge is mutually excluded from regions of activated Tyr(397)-FAK. LKB1-compromised cells lack directional persistence compared with wild-type cells, but this is restored through subsequent pharmacological FAK inhibition or depletion, showing that cell directionality is mediated through LKB1-FAK signaling. Live cell confocal imaging reveals that LKB1-compromised cells lack normal FAK site maturation and turnover, suggesting that defects in adhesion and directional persistence are caused by aberrant adhesion dynamics. Furthermore, re-expression of full-length wild-type or the LKB1 N-terminal domain repressed FAK activity, whereas the kinase domain or C-terminal domain alone did not, indicating that FAK suppression is potentially regulated through the LKB1 N-terminal domain. Based upon these results, we conclude that LKB1 serves as a FAK repressor to stabilize focal adhesion sites, and when LKB1 function is compromised, aberrant FAK signaling ensues, resulting in rapid FAK site maturation and poor directional persistence.
Highlights
LKB1 is a serine/threonine kinase important for cell polarity and motility
We show that cells stably depleted of LKB1 or its co-activator STRAD␣ have increased phosphorylation of focal adhesion kinase (FAK) at Tyr397/Tyr861 and enhanced adhesion to fibronectin
LKB1-compromised cells lack directional persistence compared with wildtype cells, but this is restored through subsequent pharmacological FAK inhibition or depletion, showing that cell directionality is mediated through LKB1-FAK signaling
Summary
LKB1 is a serine/threonine kinase important for cell polarity and motility. Results: LKB1 loss causes focal adhesion kinase hyperactivation and aberrant cell motility. Re-expression of full-length wildtype or the LKB1 N-terminal domain repressed FAK activity, whereas the kinase domain or C-terminal domain alone did not, indicating that FAK suppression is potentially regulated through the LKB1 N-terminal domain Based upon these results, we conclude that LKB1 serves as a FAK repressor to stabilize focal adhesion sites, and when LKB1 function is compromised, aberrant FAK signaling ensues, resulting in rapid FAK site maturation and poor directional persistence. Genome-wide analyses of primary and metastatic de novo lung cancers with LKB1 loss show increased metastatic disease and a disruption in adhesion signaling [36, 37] We build upon these findings to determine how LKB1 regulates FAK and to test the central hypothesis that LKB1 inactivation promotes aberrant cell migration through uncontrolled adhesion signaling. We conclude that LKB1 serves as a FAK repressor, and when LKB1 is absent, aberrant FAK signaling ensues, resulting in rapid FAK site turnover and lack of directional persistence
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