title: Microtubule affinity-regulating kinase 2 (MARK2) turns on phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) at Thr-313, a mutation site in Parkinson disease: effects on mitochondrial transport.
abstract: The kinase MARK2/Par-1 plays key roles in several cell processes, including neurodegeneration such as Alzheimer disease by phosphorylating tau and detaching it from microtubules. In search of interaction partners of MARK2, we identified phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1), which is important for the survival of neurons and whose mutations are linked to familial Parkinson disease (PD). MARK2 phosphorylated and activated the cleaved form of PINK1 (ΔN-PINK1; amino acids 156-581). Thr-313 was the primary phosphorylation site, a residue mutated to a non-phosphorylatable form (T313M) in a frequent variant of PD. Mutation of Thr-313 to Met or Glu in PINK1 showed toxic effects with abnormal mitochondrial distribution in neurons. MARK2 and PINK1 were found to colocalize with mitochondria and regulate their transport. ΔN-PINK1 promoted anterograde transport and increased the fraction of stationary mitochondria, whereas full-length PINK1 promoted retrograde transport. In both cases, MARK2 enhanced the effects. The results identify MARK2 as an upstream regulator of PINK1 and ΔN-PINK1 and provide insights into the regulation of mitochondrial trafficking in neurons and neurodegeneration in PD.
authors.affiliation: Max Planck Unit for Structural Molecular Biology, c/o Deutsches Elektronen Synchrotron (DESY), Notkestrasse 85, 22607 Hamburg, Germany. matenia@mpasmb.desy.de
authors.forename: Dorthe
authors.initials: D
authors.lastname: Matenia
authors.forename: Cindy
authors.initials: C
authors.lastname: Hempp
authors.forename: Thomas
authors.initials: T
authors.lastname: Timm
authors.forename: Annika
authors.initials: A
authors.lastname: Eikhof
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Mandelkow
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001693:Biological Transport, Active / Q000235:genetics; D016466:CHO Cells; D002470:Cell Survival; D006224:Cricetinae; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D020125:Mutation, Missense; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D016716:PC12 Cells; D010300:Parkinson Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D018411:Spodoptera; D013912:Threonine; D000099202:PTEN-Induced Putative Kinase
chemical_list: D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D013912:Threonine; D000099202:PTEN-Induced Putative Kinase; C094670:MARK2 protein, human; C105549:MARK2 protein, rat