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)

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; - inhibition is independent of the kinase activity of 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 Cofactor: Mg⁺² (putative) 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: - named isoforms=16 - alternative promoter usage: 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

Properties

SIZE: entity length = 788 aa MW = 88 kD COMPARTMENT: cytoplasm STATE: active state MOTIF: Ser phosphorylation site {S29} Ser phosphorylation site {S40} Thr phosphorylation site {T42} Ser phosphorylation site {S43} kinase domain SITE: 53-304 MOTIF: ATP-binding site NAME: ATP-binding site SITE: 59-67 Thr phosphorylation site {T58} ATP-binding site NAME: ATP-binding site SITE: 82-82 Ser phosphorylation site {S91} Ser phosphorylation site {S92} Ser phosphorylation site {S93} aspartate residue {D175} Ser phosphorylation site {S197} Thr phosphorylation site {T208} Ser phosphorylation site {S212} Ser phosphorylation site {S274} Thr phosphorylation site {T275} Thr phosphorylation site {T294} UBA domain {323-362} Ser phosphorylation site {S365} Ser phosphorylation site {S390} Ser phosphorylation site {S409} Thr phosphorylation site {T419} Ser phosphorylation site {S420} Ser phosphorylation site {S422} Tyr phosphorylation site {Y423} Ser phosphorylation site {S456} Thr phosphorylation site {T469} Ser phosphorylation site {S471} Ser phosphorylation site {S479} Ser phosphorylation site {S483} Ser phosphorylation site {S486} Ser phosphorylation site {S493} Ser phosphorylation site {S533} Ser phosphorylation site {S569} Ser phosphorylation site {S571} Ser phosphorylation site {S576} Thr phosphorylation site {T596} Ser phosphorylation site {S619} Ser phosphorylation site {S621} Ser phosphorylation site {S631} Thr phosphorylation site {T667} Ser phosphorylation site {S722} KA1 {739-788}

Database Correlations

OMIM 600526 UniProt Q7KZI7 PFAM correlations Entrez Gene 2011 Kegg hsa:2011 ENZYME 2.7.11.26

References

UniProt :accession Q7KZI7