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serine/threonine protein kinase MARK1; MAP/microtubule affinity-regulating kinase 1; PAR1 homolog c; par-1c; par1c (MARK1, KIAA1477, MARK)

Function: - serine/threonine protein kinase involved in cell polarity & microtubule dynamics regulation - phosphorylates DCX, MAP2, MAP4 & MAPT/TAU - involved in cell polarity by phosphorylating the microtubule- associated proteins MAP2, MAP4 & MAPT/TAU at KXGS motifs, causing detachment from microtubules, & their disassembly - involved in regulation of neuronal migration through its dual activities in regulating cellular polarity & microtubule dynamics, possibly by phosphorylating & regulating DCX - also acts as a positive regulator of Wnt signaling, probably by mediating phosphorylation of dishevelled proteins (DVL1, DVL2 &/or DVL3) - inhibited by phosphorylation at Ser-219 - activated by phosphorylation on Thr-215 - phosphorylation at Thr-613 by PRKCZ/aPKC in polarized epithelial cells inhibits the kinase activity (putative) - phosphorylated at Thr-215 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase & CAB39 - phosphorylation at Thr-215 by TAOK1 activates the kinase activity, leading to phosphorylation & detachment of MAPT/TAU from microtubules - phosphorylation at Ser-219 by GSK3-beta (GSK3B) inhibits the kinase activity - binds phosphatidic acid (PA), phosphatidylserine (PtdSer) & phosphatidylinositol-4,5-bisphosphate (Ptdins(4,5)P2) Cofactor: Mg+2 (putative) Structure: - the UBA domain does not seem to bind ubiquitin & might play a role in regulating the enzyme conformation & localization - activation of the kinase activity following phosphorylation at Thr-208 is accompanied by a conformational change that alters the orientation of the UBA domain with respect to the catalytic domain (putative) - the KA1 domain mediates binding to phospholipids & targeting to membranes - belongs to the protein kinase superfamily, CAMK Ser/Thr protein kinase family, SNF1 subfamily - contains 1 KA1 (kinase-associated) domain - contains 1 protein kinase domain - contains 1 UBA domain Compartment: - cell membrane; peripheral membrane protein - cytoplasm, cytoskeleton (putative) - appears to localize to an intracellular network (putative) Alternative splicing: named isoforms=3 Expression: - highly expressed in heart, skeletal muscle, brain, fetal brain & fetal kidney Pathology: - genetic variations in MARK1 may be associated with susceptibility to autism & autism spectrum disorders - MARK1 is overexpressed in the prefrontal cortex of patients with autism & causes changes in the function of cortical dendrites - phosphorylation of MAPT/tau by MARK1 could play a role in early steps of Alzheimer disease [2]

General

MAP/microtubule affinity-regulating kinase

Properties

SIZE: entity length = 795 aa MW = 89 kD COMPARTMENT: cytoplasm STATE: active state MOTIF: Thr phosphorylation site {T5} Ser phosphorylation site {S46} kinase domain SITE: 60-311 MOTIF: ATP-binding site NAME: ATP-binding site SITE: 66-74 ATP-binding site NAME: ATP-binding site SITE: 89-89 aspartate residue {D182} Thr phosphorylation site {T215} Ser phosphorylation site {S219} UBA domain {325-370} Ser phosphorylation site {S394} Ser phosphorylation site {S403} Ser phosphorylation site {S423} Ser phosphorylation site {S463} Ser phosphorylation site {S468} Ser phosphorylation site {S470} Ser phosphorylation site {S475} Ser phosphorylation site {S588} Thr phosphorylation site {T596} Thr phosphorylation site {T613} Ser phosphorylation site {S633} Ser phosphorylation site {S649} Ser phosphorylation site {S666} KA1 {746-795}

Database Correlations

OMIM correlations UniProt Q9P0L2 PFAM correlations Entrez Gene 4139 Kegg hsa:4139 ENZYME correlations

References

  1. UniProt :accession Q9P0L2
  2. Chin JY et al Microtubule-affinity regulating kinase (MARK) is tightly associated with neurofibrillary tangles in Alzheimer brain: a fluorescence resonance energy transfer study. J Neuropathol Exp Neurol. 2000 Nov;59(11):966-71. PMID: 11089574