Leucine-rich repeat kinase 2 mutants I2020T and G2019S exhibit altered kinase inhibitor sensitivity

Reichling, Laurie J.; Riddle, Steven M.

doi:10.1016/j.bbrc.2009.04.098

Cited by 26 publications

(29 citation statements)

References 14 publications

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“…It has been reported that the I2020T mutant exhibits resistance toward ATP competitive inhibitors due to its small K ATP (49). We were able to replicate this finding using an ATP competitive inhibitor GSK3-XIII (Table 3).…”

Section: Discussionsupporting

confidence: 63%

The Parkinson Disease-linked LRRK2 Protein Mutation I2020T Stabilizes an Active State Conformation Leading to Increased Kinase Activity

Ray

Bender

Kang

et al. 2014

Journal of Biological Chemistry

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Background: LRRK2 has emerged as one of the most relevant players in Parkinson disease pathogenesis. Results: Enzyme kinetic and modeling studies elucidate the effect of the LRRK2 I2020T mutant on kinase activity. Conclusion: The I2020T mutant stabilizes the active conformation and leads to increased kinase activity. As a result, it binds to type II inhibitors competitively. Significance: This study may contribute to the development of new classes of inhibitors of LRRK2.

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Section: Discussionsupporting

confidence: 63%

The Parkinson Disease-linked LRRK2 Protein Mutation I2020T Stabilizes an Active State Conformation Leading to Increased Kinase Activity

Ray

Bender

Kang

et al. 2014

Journal of Biological Chemistry

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“…Other kinase inhibitors have recently been reported to inhibit LRRK2 kinase activity with similar potency to those described here 12–15. Since an authentic substrate of LRRK2 has yet to be identified, there should be a note of caution regarding the physiological relevance of the screens used in this and related studies based on autophosphorylation and artificial substrates.…”

mentioning

confidence: 73%

Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's disease

Lee

Shin

Vankampen

et al. 2010

Nat Med

342

381

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Leucine rich repeat kinase 2 (LRRK2) mutations are a common cause of Parkinson’s disease (PD). Here, we identify inhibitors of LRRK2 kinase, which are protective in in vitro and in vivo models of LRRK2-induced neurodegeneration. These results establish that LRRK2-induced degeneration of neurons in vivo is kinase dependent and that LRRK2 kinase inhibition provides a potential new neuroprotective paradigm for the treatment of PD.

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“…The finding that the LRRK2[G2019S] mutant was 2–4-fold more sensitive H-1152, Y-27632 and sunitinib than the wild-type LRRK2 also indicates that it may be possible to develop compounds that have greater potency towards the PD mutant. It has also been reported that the LRRK2[G2019S] and LRRK2[I202T] mutants that possess elevated activity were also moderately more sensitive to a panel of non-selective kinase inhibitors [40]. If compounds that specifically inhibited PD mutant forms of LRRK2 could be elaborated, they might have lower side effects and not suppress the normal functions of wild-type LRRK2.…”

Section: Discussionmentioning

confidence: 99%

Substrate specificity and inhibitors of LRRK2, a protein kinase mutated in Parkinson's disease

Nichols

Dzamko

Hutti

et al. 2009

Biochemical Journal

188

242

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The LRRK2 (leucine-rich repeat protein kinase-2) is mutated in a significant number of Parkinson’s disease patients, but little is known about its regulation and function. A common mutation changing Gly2019 to serine enhances catalytic activity, suggesting that small-molecule inhibitors might have utility in treating Parkinson’s disease. We employed various approaches to explore the substrate-specificity requirements of LRRK2 and elaborated a peptide substrate termed Nictide, that had 20-fold lower Km and nearly 2-fold higher Vmax than the widely deployed LRRKtide substrate. We demonstrate that LRRK2 has marked preference for phosphorylating threonine over serine. We also observed that several ROCK (Rho kinase) inhibitors such as Y-27632 and H-1152, suppressed LRRK2 with similar potency to which they inhibited ROCK2. In contrast, GSK429286A, a selective ROCK inhibitor, did not significantly inhibit LRRK2. We also identified a mutant LRRK2[A2016T] that was normally active, but resistant to H-1152 and Y-27632, as well as sunitinib, a structurally unrelated multikinase inhibitor that, in contrast with other compounds, suppresses LRRK2, but not ROCK. We have also developed the first sensitive antibody that enables measurement of endogenous LRRK2 protein levels and kinase activity as well as shRNA (short hairpin RNA) methods to reduce LRRK2 expression. Finally, we describe a pharmacological approach to validate whether substrates are phosphorylated by LRRK2 and use this to provide evidence that LRRK2 may not be rate-limiting for the phosphorylation of the proposed substrate moesin. The findings of the present study will aid with the investigation of LRRK2.

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Leucine-rich repeat kinase 2 mutants I2020T and G2019S exhibit altered kinase inhibitor sensitivity

Cited by 26 publications

References 14 publications

The Parkinson Disease-linked LRRK2 Protein Mutation I2020T Stabilizes an Active State Conformation Leading to Increased Kinase Activity

The Parkinson Disease-linked LRRK2 Protein Mutation I2020T Stabilizes an Active State Conformation Leading to Increased Kinase Activity

Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's disease

Substrate specificity and inhibitors of LRRK2, a protein kinase mutated in Parkinson's disease

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