Coordinated cell motility is regulated by a combination of LKB1 farnesylation and kinase activity

Abstract

Cell motility requires the precise coordination of cell polarization, lamellipodia formation, adhesion, and force generation. LKB1 is a multi-functional serine/threonine kinase that associates with actin at the cellular leading edge of motile cells and suppresses FAK. We sought to understand how LKB1 coordinates these multiple events by systematically dissecting LKB1 protein domain function in combination with live cell imaging and computational approaches. We show that LKB1-actin colocalization is dependent upon LKB1 farnesylation leading to RhoA-ROCK-mediated stress fiber formation, but membrane dynamics is reliant on LKB1 kinase activity. We propose that LKB1 kinase activity controls membrane dynamics through FAK since loss of LKB1 kinase activity results in morphologically defective nascent adhesion sites. In contrast, defective farnesylation mislocalizes nascent adhesion sites, suggesting that LKB1 farnesylation serves as a targeting mechanism for properly localizing adhesion sites during cell motility. Together, we propose a model where coordination of LKB1 farnesylation and kinase activity serve as a multi-step mechanism to coordinate cell motility during migration.

Endogenous Control Mechanisms of FAK and PYK2 and Their Relevance to Cancer Development

“…The liver kinase 1 (LKB1) or STK11 is a multifunctional serine/threonine kinase that links energy sensing and cell polarity [ 92 , 93 , 94 ]. In particular, LKB1 stabilizes cell polarity under energy stress.…”

“…In particular, LKB1 stabilizes cell polarity under energy stress. Given that loss of cell polarity increases undirectional ‘exploratory’ migration, LKB1 controls cell movements during embryogenesis and wound healing [ 92 , 93 , 94 ]. LKB1 also counteracts cancer cell metastasis and is the third most frequently mutated gene in lung adenocarcinoma [ 95 , 96 , 97 ].…”

Endogenous Control Mechanisms of FAK and PYK2 and Their Relevance to Cancer Development and Therapy

“…The liver kinase 1 (LKB1) or STK11 is a multifunctional serine/threonine kinase that links energy sensing and cell polarity [81][82][83]. In particular, LKB1 stabilizes cell polarity under energy stress.…”

“…Given that loss of cell polarity increases undirectional 'exploratory' migration, LKB1 controls cell movements during embryogenesis and wound healing [81][82][83]. LKB1 also counteracts cancer cell metastasis and is the third most frequently mutated gene in lung adenocarcinoma [84][85][86].…”

“…Rather than through phosphosylation of its activation loop, LKB1 (Figure 3) is activated allosterically through an association with the pseudo-kinase STRADα, which is tethered to LKB1 by the scaffolding protein MO25α [87]. In addition, LKB1 activity and localization are affected by post-translational modification [81,83]. SUMOlyation of LKB1 K178, in response to energy stress, promotes the interaction between LKB1 and the AMP-activated protein kinase (AMPK).…”