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

More general terms

• MAP/microtubule affinity-regulating kinase

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=4139
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:4139
• OMIM: https://mirror.omim.org/entry/209850
• OMIM: https://mirror.omim.org/entry/606511
• UniProt: http://www.uniprot.org/uniprot/Q9P0L2.html