serine/threonine protein kinase N1; protease-activated kinase 1; PAK-1; protein kinase C-like 1; protein kinase C-like PKN; protein kinase PKN-alpha; protein-kinase C-related kinase 1; serine-threonine protein kinase N (PKN1, PKN, PRK1, PRKCL1)

Function

• PKC-related serine/threonine protein kinase
• role in various processes such as
  • regulation of the intermediate filaments of the actin cytoskeleton
  • transcription regulation
• regulates the cytoskeletal network by phosphorylating proteins such as VIM & neurofilament proteins NEFH, NEFL & NEFM, leading to inhibition of their polymerization
• phosphorylates Ser-575, Ser-637 & Ser-669 of MAPT/Tau, lowering its ability to bind to microtubules, resulting in disruption of tubulin assembly
• acts as a key coactivator of androgen receptor (AR)-dependent transcription, by being recruited to AR target genes & specifically mediating phosphorylation of Thr-11 of histone H3 (H3T11ph), a specific tag for epigenetic transcriptional activation that promotes demethylation of histone H3 Lys-9 (H3K9me) by KDM4C/JMJD2C
• phosphorylates HDAC5, HDAC7 & HDAC9, leading to impair their import in the nucleus
• phosphorylates Thr-38 of PPP1R14A, Ser-159, Ser-163 & Ser-170 of MARCKS, & GFAP
• able to phosphorylate RPS6 in vitro
• kinase activity is activated upon binding to Rho proteins (RHOA, RHOB & RAC1). activated by lipids, particularly cardiolipin & to a lesser extent by other acidic phospholipids
• activated by caspase-3 (CASP3) cleavage during apoptosis
• two specific sites, Thr-774 (activation loop of the kinase domain) & Ser-916 (turn motif), need to be phosphorylated for its full activation
• autophosphorylated; preferably on serine
• activated by limited proteolysis with trypsin
• interacts with ZA20D3 (putative)
• interacts with ANDR
• interacts with PRKCB
• interacts (via REM 1 & REM 2 repeats) with RAC1
• interacts (via REM 1 repeat) with RHOA interacts with RHOB
• in case of infection, interacts with S typhimurium protein sspH1

Kinetic parameters:

• KM=20.6 uM for HDAC5

Structure

• the C1 domain does not bind the diacylglycerol (DAG)
• belongs to the protein kinase superfamily, AGC Ser/Thr
• protein kinase family, PKC subfamily
• contains 1 AGC-kinase C-terminal domain
• contains 1 C2 domain
• contains 1 protein kinase domain
• contains 3 REM (Hr1) repeats

Compartment

• cytoplasm, nucleus, endosome, cell membrane
• associates with chromatin (ligand-dependent)
• localization to endosomes is mediated via its interaction with RHOB
• association with the cell membrane is dependent on Ser-374 phosphorylation

Alternative splicing

named isoforms=3

Expression

• found ubiquitously
• expressed in heart, brain, placenta, lung, skeletal muscle, kidney & pancreas

More general terms

• protease-activated kinase

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=5585
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:5585
• OMIM: https://mirror.omim.org/entry/601032
• UniProt: http://www.uniprot.org/uniprot/Q16512.html