serine/threonine protein kinase MARK2; ELKL motif kinase 1; EMK-1; MAP/microtubule affinity-regulating kinase 2; PAR1 homolog; PAR1 homolog b; par-1b; par1b (MARK2 EMK1)
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Function
- serine/threonine protein kinase
- involved in cell polarity & microtubule dynamics regulation
- phosphorylates CRTC2/TORC2, DCX, HDAC7, KIF13B, MAP2, MAP4, MAPT/TAU, & RAB11FIP2
- role in cell polarity by phosphorylating the microtubule-associated proteins MAP2, MAP4 & MAPT/TAU at KXGS motifs, causing detachment from microtubules, & their disassembly
- regulates epithelial cell polarity by phosphorylating RAB11FIP2
- role in regulation of neuronal migration through its dual activities in regulating cellular polarity & microtubule dynamics, possibly by phosphorylating & regulating DCX
- regulates axogenesis by phosphorylating KIF13B, promoting interaction between KIF13B & 14-3-3 & inhibiting microtubule- dependent accumulation of KIF13B
- also required for neurite outgrowth & establishment of neuronal polarity
- regulates localization & activity of some histone deacetylases by mediating phosphorylation of HDAC7, promoting subsequent interaction between HDAC7 & 14-3-3 & export from the nucleus
- positive regulator of the Wnt signaling pathway, probably by mediating phosphorylation of dishevelled proteins (DVL1, DVL2 &/or DVL3)
- modulates developmental decision to build a columnar versus a hepatic epithelial cell apparently by promoting a switch from a direct to a transcytotic mode of apical protein delivery
- essential for the asymmetric development of membrane domains of polarized epithelial cells
- inhibited by PAK7/PAK5;
- activated by phosphorylation on Thr-208
- inhibited by phosphorylation at Ser-212 & Thr-596 the kinase substrate-binding site
- autophosphorylated
- phosphorylated at Thr-208 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase & CAB39
- phosphorylation at Thr-208 by TAOK1 activates the kinase activity, leading to phosphorylation & detachment of MAPT/TAU from microtubules
- phosphorylation at Ser-212 by GSK3- beta (GSK3B) inhibits the kinase activity
- phosphorylation by CaMK1 promotes activity & is required to promote neurite outgrowth
- phosphorylation at Thr-596 by PRKCZ/aPKC in polarized epithelial cells inhibits the kinase activity & promotes binding to 14-3-3 protein YWHAZ, leading to relocation from cell membrane to cytoplasm
- interacts with PAK7/PAK5 inhibiting the protein kinase activity (putative)
- interacts (when phosphorylated at Thr-596) with YWHAZ
Inhibition:
- inhibited by hymenialdisine
- specifically inhibited by the H pylori CagA peptide FPLKRHDKVDDLSK that mimics host substrates & binds to
Structure
- homodimer
- 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
- the KA1 domain mediates binding to phospholipids & targeting to membranes (putative)
- 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, cytoplasm
- phosphorylation at Thr-596 by PRKCZ/aPKC & subsequent interaction with 14-3-3 protein YWHAZ promotes relocation from the cell membrane to the cytoplasm
Alternative splicing
Expression
- high levels of expression in heart, brain, skeletal muscle & pancreas
- lower levels observed in lung, liver & kidney
Pathology
- in case of infection, interacts with H pylori CagA, leading to inhibit kinase activity & junctional & polarity defects