mTOR independent alteration in ULK1 Ser758 phosphorylation following chronic LRRK2 kinase inhibition

Unc-51 Like Kinase 1 (ULK1) is a critical regulator of the biogenesis of autophagosomes, the central component of the catabolic macroautophagy pathway. Regulation of ULK1 activity is dependent upon several phosphorylation events acting to repress or activate the enzymatic function of this protein. Phosphorylation of Ser758 ULK1 has been linked to repression of autophagosome biogenesis and was thought to be exclusively dependent upon mTOR complex 1 kinase activity. In the present study, a novel regulation of Ser758 ULK1 phosphorylation is reported following prolonged inhibition of the Parkinson’s disease linked protein leucine rich repeat kinase 2 (LRRK2). Here, modulation of Ser758 ULK1 phosphorylation following LRRK2 inhibition is decoupled from the repression of autophagosome biogenesis and independent of mTOR complex 1 activity.

[1]  M. Cookson,et al.  mTOR independent regulation of macroautophagy by Leucine Rich Repeat Kinase 2 via Beclin-1 , 2016, Scientific Reports.

[2]  N. Ktistakis,et al.  Digesting the Expanding Mechanisms of Autophagy. , 2016, Trends in cell biology.

[3]  X. Zhong,et al.  Sustained activation of mTORC1 in macrophages increases AMPKα-dependent autophagy to maintain cellular homeostasis , 2016, BMC Biochemistry.

[4]  S. Costantini,et al.  Blue-Print Autophagy: Potential for Cancer Treatment , 2016, Marine drugs.

[5]  C. Kraft,et al.  Regulation of Autophagy By Signaling Through the Atg1/ULK1 Complex. , 2016, Journal of molecular biology.

[6]  Sangeeta Khare,et al.  Guidelines for the use and interpretation of assays formonitoring autophagy (3rd edition) , 2016 .

[7]  C. Campochiaro,et al.  Guidelines for the use and interpretation of diagnostic methods in adult food allergy , 2015, Clinical and Molecular Allergy.

[8]  Xuejun Jiang,et al.  Regulation of autophagy by coordinated action of mTORC1 and protein phosphatase 2A , 2015, Nature Communications.

[9]  Angeleen Fleming,et al.  Compromised autophagy and neurodegenerative diseases , 2015, Nature Reviews Neuroscience.

[10]  J. Schapansky,et al.  Membrane recruitment of endogenous LRRK2 precedes its potent regulation of autophagy. , 2014, Human molecular genetics.

[11]  F. J. Romero,et al.  The LRRK2 inhibitor GSK2578215A induces protective autophagy in SH-SY5Y cells: involvement of Drp-1-mediated mitochondrial fission and mitochondrial-derived ROS signaling , 2014, Cell Death and Disease.

[12]  Chuong B. Do,et al.  Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease , 2014, Nature Genetics.

[13]  Longxuan Li,et al.  ULK1 translocates to mitochondria and phosphorylates FUNDC1 to regulate mitophagy , 2014, EMBO reports.

[14]  Darío,et al.  GSK 2578215 A ; A potent and highly selective 2-arylmethyloxy-5-substitutent-N-arylbenzamide LRRK 2 kinase inhibitor , 2014 .

[15]  B. Joseph,et al.  The return of the nucleus: transcriptional and epigenetic control of autophagy , 2013, Nature Reviews Molecular Cell Biology.

[16]  P. Giunti,et al.  Inhibition of LRRK2 kinase activity stimulates macroautophagy , 2013, Biochimica et biophysica acta.

[17]  Michael J. Devine,et al.  Pathogenic Parkinson’s disease mutations across the functional domains of LRRK2 alter the autophagic/lysosomal response to starvation☆ , 2013, Biochemical and biophysical research communications.

[18]  A. Tee,et al.  The kinase triad, AMPK, mTORC1 and ULK1, maintains energy and nutrient homoeostasis. , 2013, Biochemical Society transactions.

[19]  A. Harris,et al.  Transcriptional up-regulation of ULK1 by ATF4 contributes to cancer cell survival. , 2013, The Biochemical journal.

[20]  S. Tooze,et al.  Regulation of nutrient-sensitive autophagy by uncoordinated 51-like kinases 1 and 2 , 2013, Autophagy.

[21]  N. Gray,et al.  GSK2578215A; a potent and highly selective 2-arylmethyloxy-5-substitutent-N-arylbenzamide LRRK2 kinase inhibitor. , 2012, Bioorganic & medicinal chemistry letters.

[22]  Sheila M. Thomas,et al.  AMPK-dependent phosphorylation of ULK1 regulates ATG9 localization , 2012, Autophagy.

[23]  M. Memo,et al.  Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease , 2012, EMBO molecular medicine.

[24]  Robert Clarke,et al.  Guidelines for the use and interpretation of assays for monitoring autophagy , 2012 .

[25]  S. Wesselborg,et al.  The incredible ULKs , 2012, Cell Communication and Signaling.

[26]  G. Churchill,et al.  Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP , 2011, Human molecular genetics.

[27]  H. Cai,et al.  Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway , 2012, Molecular Neurodegeneration.

[28]  S. Wesselborg,et al.  Role of AMPK-mTOR-Ulk1/2 in the Regulation of Autophagy: Cross Talk, Shortcuts, and Feedbacks , 2011, Molecular and Cellular Biology.

[29]  N. Gray,et al.  Characterization of a selective inhibitor of the Parkinson’s disease kinase LRRK2 , 2011, Nature chemical biology.

[30]  M. Demirci.  Comprehensive Clinical Nephrology 3rd Edition , 2011 .

[31]  Richard Wade-Martins,et al.  LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model. , 2009, Human molecular genetics.

[32]  C. Chu,et al.  Role of autophagy in G2019S‐LRRK2‐associated neurite shortening in differentiated SH‐SY5Y cells , 2008, Journal of neurochemistry.

[33]  C. Ross,et al.  Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[34]  Thomas Meitinger,et al.  Mutations in LRRK2 Cause Autosomal-Dominant Parkinsonism with Pleomorphic Pathology , 2004, Neuron.

[35]  Andrew Lees,et al.  Cloning of the Gene Containing Mutations that Cause PARK8-Linked Parkinson's Disease , 2004, Neuron.

[36]  Kazuya Nagano,et al.  Tor-Mediated Induction of Autophagy via an Apg1 Protein Kinase Complex , 2000, The Journal of cell biology.